Literature

This section presents a list of the latest published scientific journal articles and preprints on COVID-19 and SARS-CoV-2 where at least one author has a Spanish affiliation. Items have been fetched from an automatic daily search from Europe PMC completed with other elements manually curated and uploaded from researchers.

There are filters at your disposal to navigate the list, i.e. publications with acknowledged funding to the “Fondo COVID19” extraordinary funds. Note that some articles have additional available data that have been curated manually and as such may not be exhaustive.

You can help us enriching this section by adding new papers not listed below or available associated data to existing ones (datasets, code repositories…) by filling in this formulaire. Please make sure that the information is not already in the table below and that the publication has at least one author affiliated in Spain.

Last update: 2024-05-23
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Publications Published Year Funder Publication type Available abstract Available related data DOI Title Authors Journal
The target landscape of N4-hydroxycytidine based on its chemical neighborhood
Jordi Mestres
preprint  bioRxiv
DOI: 10.1101/2020.03.30.016485
N4-hydroxycytidine (NHC) has been recently reported to have promising antiviral activity against SARS-CoV-2. To join worldwide efforts in identifying potential drug targets against this pandemic, the target landscape of NHC was defined by extracting all known targets of its chemical neighborhood, including drugs, analogues, and metabolites, and by performing target predictions from two independent platforms, following the recent Public Health Assessment via Structural Evaluation (PHASE) protocol. The analysis provides a list of over 30 protein targets that could be useful in future design activities of new COVID-19 antivirals. The relevance for existing drugs within the same chemical space, such as remdesivir, is also discussed.
2020-04-01 2020 other preprint abstract-available data-available 10.1101/2020.03.30.016485 The target landscape of N4-hydroxycytidine based on its chemical neighborhood Jordi Mestres bioRxiv
Simulating SARS-CoV-2 epidemics by region-specific variables and modeling contact tracing app containment
Alberto Ferrari, Enrico Santus, Davide Cirillo, Miguel Ponce-de-Leon, [...], Alfonso Valencia
npj Digital Medicine, volume 4, Article number: 9 (2021)
DOI: 10.1038/s41746-020-00374-4
Targeted contact-tracing through mobile phone apps has been proposed as an instrument to help contain the spread of COVID-19 and manage the lifting of nation-wide lock-downs currently in place in USA and Europe. However, there is an ongoing debate on its potential efficacy, especially in light of region-specific demographics. We built an expanded SIR model of COVID-19 epidemics that accounts for region-specific population densities, and we used it to test the impact of a contact-tracing app in a number of scenarios. Using demographic and mobility data from Italy and Spain, we used the model to simulate scenarios that vary in baseline contact rates, population densities, and fraction of app users in the population. Our results show that, in support of efficient isolation of symptomatic cases, app-mediated contact-tracing can successfully mitigate the epidemic even with a relatively small fraction of users, and even suppress altogether with a larger fraction of users. However, when regional differences in population density are taken into consideration, the epidemic can be significantly harder to contain in higher density areas, highlighting potential limitations of this intervention in specific contexts. This work corroborates previous results in favor of app-mediated contact-tracing as mitigation measure for COVID-19, and draws attention on the importance of region-specific demographic and mobility factors to achieve maximum efficacy in containment policies.
2021-01-14 2021 other article abstract-available data-available 10.1038/s41746-020-00374-4 Simulating SARS-CoV-2 epidemics by region-specific variables and modeling contact tracing app containment Alberto Ferrari, Enrico Santus, Davide Cirillo, Miguel Ponce-de-Leon, Nicola Marino, Maria Teresa Ferretti, Antonella Santuccione Chadha, Nikolaos Mavridis, Alfonso Valencia npj Digital Medicine, volume 4, Article number: 9 (2021)
RNA-Dependent RNA Polymerase From SARS-CoV-2. Mechanism Of Reaction And Inhibition By Remdesivir
Juan Aranda, Modesto Orozco
preprint  bioRxiv
DOI: 10.1101/2020.06.21.163592
We combine sequence analysis, molecular dynamics and hybrid quantum mechanics/molecular mechanics simulations to obtain the first description of the mechanism of reaction of SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) and of the inhibition of the enzyme by Remdesivir. Despite its evolutionary youth, the enzyme is highly optimized to have good fidelity in nucleotide incorporation and a good catalytic efficiency. Our simulations strongly suggest that Remdesivir triphosphate (the active form of drug) is incorporated into the nascent RNA replacing ATP, leading to a duplex RNA which is structurally very similar to an unmodified one. We did not detect any reason to explain the inhibitory activity of Remdesivir at the active site. Displacement of the nascent Remdesivir-containing RNA duplex along the exit channel of the enzyme can occur without evident steric clashes which would justify delayed inhibition. However, after the incorporation of three more nucleotides we found a hydrated Serine which is placed in a perfect arrangement to react through a Pinner’s reaction with the nitrile group of Remdesivir. Kinetic barriers for crosslinking and polymerization are similar suggesting a competition between polymerization and inhibition. Analysis of SARS-CoV-2 mutational landscape and structural analysis of polymerases across different species support the proposed mechanism and suggest that virus has not explored yet resistance to Remdesivir inhibition.
2020-06-21 2020 other preprint abstract-available data-available 10.1101/2020.06.21.163592 RNA-Dependent RNA Polymerase From SARS-CoV-2. Mechanism Of Reaction And Inhibition By Remdesivir Juan Aranda, Modesto Orozco bioRxiv
MasterOfPores: A Workflow for the Analysis of Oxford Nanopore Direct RNA Sequencing Datasets
Luca Cozzuto, Huanle Liu, Leszek P. Pryszcz, Toni Hermoso Pulido, [...], Eva Maria Novoa
Front. Genet. 11:211
DOI: 10.3389/fgene.2020.00211
The direct RNA sequencing platform offered by Oxford Nanopore Technologies allows for direct measurement of RNA molecules without the need of conversion to complementary DNA, fragmentation or amplification. As such, it is virtually capable of detecting any given RNA modification present in the molecule that is being sequenced, as well as provide polyA tail length estimations at the level of individual RNA molecules. Although this technology has been publicly available since 2017, the complexity of the raw Nanopore data, together with the lack of systematic and reproducible pipelines, have greatly hindered the access of this technology to the general user. Here we address this problem by providing a fully benchmarked workflow for the analysis of direct RNA sequencing reads, termed MasterOfPores. The pipeline starts with a pre-processing module, which converts raw current intensities into multiple types of processed data including FASTQ and BAM, providing metrics of the quality of the run, quality-filtering, demultiplexing, base-calling and mapping. In a second step, the pipeline performs downstream analyses of the mapped reads, including prediction of RNA modifications and estimation of polyA tail lengths. Four direct RNA MinION sequencing runs can be fully processed and analyzed in 10 h on 100 CPUs. The pipeline can also be executed in GPU locally or in the cloud, decreasing the run time fourfold. The software is written using the NextFlow framework for parallelization and portability, and relies on Linux containers such as Docker and Singularity for achieving better reproducibility. The MasterOfPores workflow can be executed on any Unix-compatible OS on a computer, cluster or cloud without the need of installing any additional software or dependencies, and is freely available in Github (https://github.com/biocorecrg/master_of_pores). This workflow simplifies direct RNA sequencing data analyses, facilitating the study of the (epi)transcriptome at single molecule resolution.
2020-03-17 2020 other article abstract-available data-available 10.3389/fgene.2020.00211 MasterOfPores: A Workflow for the Analysis of Oxford Nanopore Direct RNA Sequencing Datasets Luca Cozzuto, Huanle Liu, Leszek P. Pryszcz, Toni Hermoso Pulido, Anna Delgado-Tejedor, Julia Ponomarenko, Eva Maria Novoa Front. Genet. 11:211
Functional characterization of SARS-CoV-2 infection suggests a complex inflammatory response and metabolic alterations
Lucía Trilla-Fuertes, Ricardo Ramos, Natalia Blanca-López, Elena López-Camacho, [...], Angelo Gámez-Pozo
preprint  bioRxiv
DOI: 10.1101/2020.06.22.164384
Covid-19, caused by the SARS-CoV-2 virus, has reached the category of a worldwide pandemic. Even though intensive efforts, no effective treatments or a vaccine are available. Molecular characterization of the transcriptional response in Covid-19 patients could be helpful to identify therapeutic targets. In this study, RNAseq data from peripheral blood mononuclear cell samples from Covid-19 patients and healthy controls was analyzed from a functional point of view using probabilistic graphical models. Two networks were built: one based on genes differentially expressed between healthy and infected individuals and another one based on the 2,000 most variable genes in terms of expression in order to make a functional characterization. In the network based on differentially expressed genes, two inflammatory response nodes with different tendencies were identified, one related to cytokines and chemokines, and another one related to bacterial infections. In addition, differences in metabolism, which were studied in depth using Flux Balance Analysis, were identified. SARS-CoV2-infection caused alterations in glutamate, methionine and cysteine, and tetrahydrobiopterin metabolism. In the network based on 2,000 most variable genes, also two inflammatory nodes with different tendencies between healthy individuals and patients were identified. Similar to the other network, one was related to cytokines and chemokines. However, the other one, lower in Covid-19 patients, was related to allergic processes and self-regulation of the immune response. Also, we identified a decrease in T cell node activity and an increase in cell division node activity. In the current absence of treatments for these patients, functional characterization of the transcriptional response to SARS-CoV-2 infection could be helpful to define targetable processes. Therefore, these results may be relevant to propose new treatments.
2020-09-24 2020 other preprint abstract-available data-available 10.1101/2020.06.22.164384 Functional characterization of SARS-CoV-2 infection suggests a complex inflammatory response and metabolic alterations Lucía Trilla-Fuertes, Ricardo Ramos, Natalia Blanca-López, Elena López-Camacho, Laura Martín-Pedraza, Pablo Ryan Murua, Mariana Díaz-Almirón, Carlos Llorens, Toni Gabaldón, Andrés Moya, Juan Ángel Fresno Vara, Angelo Gámez-Pozo bioRxiv
Drug repurposing for COVID-19 using machine learning and mechanistic models of signal transduction circuits related to SARS-CoV-2 infection
Carlos Loucera, Marina Esteban-Medina, Kinza Rian, Matías M. Falco, [...], María Peña-Chilet
Sig Transduct Target Ther 5, 290 (2020)
DOI: 10.1038/s41392-020-00417-y
2020-12-11 2020 other article data-available 10.1038/s41392-020-00417-y Drug repurposing for COVID-19 using machine learning and mechanistic models of signal transduction circuits related to SARS-CoV-2 infection Carlos Loucera, Marina Esteban-Medina, Kinza Rian, Matías M. Falco, Joaquín Dopazo, María Peña-Chilet Sig Transduct Target Ther 5, 290 (2020)
DatAC: A visual analytics platform to explore climate and air quality indicators associated with the COVID-19 pandemic in Spain
Jordi Martorell-Marugán, Juan Antonio Villatoro-García, Adrián García-Moreno, Raúl López-Domínguez, [...], Pedro Carmona-Sáez
Science of The Total Environment, Volume 750, 2021, 141424, ISSN 0048-9697
DOI: 10.1016/j.scitotenv.2020.141424
The coronavirus disease 2019 (COVID-19) pandemic has caused an unprecedented global health crisis, with several countries imposing lockdowns to control the coronavirus spread. Important research efforts are focused on evaluating the association of environmental factors with the survival and spread of the virus and different works have been published, with contradictory results in some cases. Data with spatial and temporal information is a key factor to get reliable results and, although there are some data repositories for monitoring the disease both globally and locally, an application that integrates and aggregates data from meteorological and air quality variables with COVID-19 information has not been described so far to the best of our knowledge. Here, we present DatAC (Data Against COVID-19), a data fusion project with an interactive web frontend that integrates COVID-19 and environmental data in Spain. DatAC is provided with powerful data analysis and statistical capabilities that allow users to explore and analyze individual trends and associations among the provided data. Using the application, we have evaluated the impact of the Spanish lockdown on the air quality, observing that NO2, CO, PM2.5, PM10 and SO2 levels decreased drastically in the entire territory, while O3 levels increased. We observed similar trends in urban and rural areas, although the impact has been more important in the former. Moreover, the application allowed us to analyze correlations among climate factors, such as ambient temperature, and the incidence of COVID-19 in Spain. Our results indicate that temperature is not the driving factor and without effective control actions, outbreaks will appear and warm weather will not substantially limit the growth of the pandemic. DatAC is available at https://covid19.genyo.es.
2020-06-23 2020 other article abstract-available data-available 10.1016/j.scitotenv.2020.141424 DatAC: A visual analytics platform to explore climate and air quality indicators associated with the COVID-19 pandemic in Spain Jordi Martorell-Marugán, Juan Antonio Villatoro-García, Adrián García-Moreno, Raúl López-Domínguez, Francisco Requena, Juan Julián Merelo, Marina Lacasaña, Juan de Dios Luna, Juan J. Díaz-Mochón, Jose A. Lorente, Pedro Carmona-Sáez Science of The Total Environment, Volume 750, 2021, 141424, ISSN 0048-9697
COVID-19 Outcomes in 4712 consecutively confirmed SARS-CoV2 cases in the city of Madrid
Sarah Heili-Frades, Pablo Minguez, Ignacio Mahillo Fernández, Tomás Prieto-Rumeau, [...], COVID FJD-TEAM
preprint  medRxiv
DOI: 10.1101/2020.05.22.20109850
There is limited information describing features and outcomes of patients requiring hospitalization for COVID19 disease and still no treatments have clearly demonstrated efficacy. Demographics and clinical variables on admission, as well as laboratory markers and therapeutic interventions were extracted from electronic Clinical Records (eCR) in 4712 SARS-CoV2 infected patients attending 4 public Hospitals in Madrid. Patients were stratified according to age and stage of severity. Using multivariate logistic regression analysis, cut-off points that best discriminated mortality were obtained for each of the studied variables. Principal components analysis and a neural network (NN) algorithm were applied. A high mortality incidence associated to age >70, comorbidities (hypertension, neurological disorders and diabetes), altered vitals such as fever, heart rhythm disturbances or elevated systolic blood pressure, and alterations in several laboratory tests. Remarkably, analysis of therapeutic options either taken individually or in combination drew a universal relationship between the use of Cyclosporine A and better outcomes as also a benefit of tocilizumab and/or corticosteroids in critically ill patients. We present a large Spanish population-based study addressing factors influencing survival in current SARS CoV2 pandemic, with particular emphasis on the effectivity of treatments. In addition, we have generated an NN capable of identifying severity predictors of SARS CoV2. A rapid extraction and management of data protocol from eCR and artificial intelligence in-house implementations allowed us to perform almost real time monitoring of the outbreak evolution.
2020-05-29 2020 other preprint abstract-available data-available 10.1101/2020.05.22.20109850 COVID-19 Outcomes in 4712 consecutively confirmed SARS-CoV2 cases in the city of Madrid Sarah Heili-Frades, Pablo Minguez, Ignacio Mahillo Fernández, Tomás Prieto-Rumeau, Antonio Herrero González, Lorena de la Fuente, María Jesús Rodríguez Nieto, Germán Peces-Barba Romero, Mario Peces-Barba, María del Pilar Carballosa de Miguel, Itziar Fernández Ormaechea, Alba Naya prieto, Farah Ezzine de Blas, Luis Jiménez Hiscock, Cesar Perez Calvo, Arnoldo Santos, Luis Enrique Muñoz Alameda, Fredeswinda Romero Bueno, Miguel Górgolas Hernández-Mora, Alfonso Cabello Úbeda, Beatriz Álvarez Álvarez, Elizabet Petkova, Nerea Carrasco, Dolores Martín Ríos, Nicolás González Mangado, Olga Sánchez Pernaute, COVID FJD-TEAM medRxiv
COVID-19 Disease Map, building a computational repository of SARS-CoV-2 virus-host interaction mechanisms
Marek Ostaszewski, Alexander Mazein, Marc E. Gillespie, Inna Kuperstein, [...], Reinhard Schneider
Sci Data 7, 136 (2020)
DOI: 10.1038/s41597-020-0477-8
2020-05-05 2020 other article data-available 10.1038/s41597-020-0477-8 COVID-19 Disease Map, building a computational repository of SARS-CoV-2 virus-host interaction mechanisms Marek Ostaszewski, Alexander Mazein, Marc E. Gillespie, Inna Kuperstein, Anna Niarakis, Henning Hermjakob, Alexander R. Pico, Egon L. Willighagen, Chris T. Evelo, Jan Hasenauer, Falk Schreiber, Andreas Dräger, Emek Demir, Olaf Wolkenhauer, Laura I. Furlong, Emmanuel Barillot, Joaquin Dopazo, Aurelio Orta-Resendiz, Francesco Messina, Alfonso Valencia, Akira Funahashi, Hiroaki Kitano, Charles Auffray, Rudi Balling, Reinhard Schneider Sci Data 7, 136 (2020)
Unraveling the molecular basis of host cell receptor usage in SARS-CoV-2 and other human pathogenic β-CoVs,
Camila Pontes, Victoria Ruiz-Serra, Rosalba Lepore, Alfonso Valencia
Computational and Structural Biotechnology Journal, Volume 19, 2021, Pages 759-766, ISSN 2001-0370.
DOI: 10.1016/j.csbj.2021.01.006
The recent emergence of the novel SARS-CoV-2 in China and its rapid spread in the human population has led to a public health crisis worldwide. Like in SARS-CoV, horseshoe bats currently represent the most likely candidate animal source for SARS-CoV-2. Yet, the specific mechanisms of cross-species transmission and adaptation to the human host remain unknown. Here we show that the unsupervised analysis of conservation patterns across the β-CoV spike protein family, using sequence information alone, can provide valuable insights on the molecular basis of the specificity of β-CoVs to different host cell receptors. More precisely, our results indicate that host cell receptor usage is encoded in the amino acid sequences of different CoV spike proteins in the form of a set of specificity determining positions (SDPs). Furthermore, by integrating structural data, in silico mutagenesis and coevolution analysis we could elucidate the role of SDPs in mediating ACE2 binding across the Sarbecovirus lineage, either by engaging the receptor through direct intermolecular interactions or by affecting the local environment of the receptor binding motif. Finally, by the analysis of coevolving mutations across a paired MSA we were able to identify key intermolecular contacts occurring at the spike-ACE2 interface. These results show that effective mining of the evolutionary records held in the sequence of the spike protein family can help tracing the molecular mechanisms behind the evolution and host-receptor adaptation of circulating and future novel β-CoVs.
2021-01-12 2021 other article abstract-available data-available 10.1016/j.csbj.2021.01.006 Unraveling the molecular basis of host cell receptor usage in SARS-CoV-2 and other human pathogenic β-CoVs, Camila Pontes, Victoria Ruiz-Serra, Rosalba Lepore, Alfonso Valencia Computational and Structural Biotechnology Journal, Volume 19, 2021, Pages 759-766, ISSN 2001-0370.
Mental health impact of the first wave of COVID-19 pandemic on Spanish healthcare workers: A large cross-sectional survey.
Jordi Alonso, Gemma Vilagut, Philippe Mortier, Montse Ferrer, [...], MINDCOVID Working group (2020)
Revista de psiquiatria y salud mental, S1888-9891(20)30128-2. Advance online publication.
DOI: 10.1016/j.rpsm.2020.12.001
INTRODUCTION: Healthcare workers are vulnerable to adverse mental health impacts of the COVID-19 pandemic. We assessed prevalence of mental disorders and associated factors during the first wave of the pandemic among healthcare professionals in Spain. METHODS: All workers in 18 healthcare institutions (6 AACC) in Spain were invited to web-based surveys assessing individual characteristics, COVID-19 infection status and exposure, and mental health status (May 5 - September 7, 2020). We report: probable current mental disorders (Major Depressive Disorder-MDD- [PHQ-8≥10], Generalized Anxiety Disorder-GAD- [GAD-7≥10], Panic attacks, Posttraumatic Stress Disorder -PTSD- [PCL-5≥7]; and Substance Use Disorder -SUD-[CAGE-AID≥2]. Severe disability assessed by the Sheehan Disability Scale was used to identify probable "disabling" current mental disorders. RESULTS: 9,138 healthcare workers participated. Prevalence of screen-positive disorder: 28.1% MDD; 22.5% GAD, 24.0% Panic; 22.2% PTSD; and 6.2% SUD. Overall 45.7% presented any current and 14.5% any disabling current mental disorder. Workers with pre-pandemic lifetime mental disorders had almost twice the prevalence than those without. Adjusting for all other variables, odds of any disabling mental disorder were: prior lifetime disorders (TUS: OR=5.74; 95%CI 2.53-13.03; Mood: OR=3.23; 95%CI:2.27-4.60; Anxiety: OR=3.03; 95%CI:2.53-3.62); age category 18-29 years (OR=1.36; 95%CI:1.02-1.82), caring "all of the time" for COVID-19 patients (OR=5.19; 95%CI: 3.61-7.46), female gender (OR=1.58; 95%CI: 1.27-1.96) and having being in quarantine or isolated (OR= 1.60; 95CI:1.31-1.95). CONCLUSIONS: One in seven Spanish healthcare workers screened positive for a disabling mental disorder during the first wave of the COVID-19 pandemic. Workers reporting pre-pandemic lifetime mental disorders, those frequently exposed to COVID-19 patients, infected or quarantined/isolated, female workers, and auxiliary nurses should be considered groups in need of mental health monitoring and support.
2020-12-20 2020 other article abstract-available data-available 10.1016/j.rpsm.2020.12.001 Mental health impact of the first wave of COVID-19 pandemic on Spanish healthcare workers: A large cross-sectional survey. Jordi Alonso, Gemma Vilagut, Philippe Mortier, Montse Ferrer, Itxaso Alayo, Andrés Aragón-Peña, Enric Aragonès, Mireia Campos, Isabel D. Cura-González, José I. Emparanza, Meritxell Espuga, Maria João Forjaz, Ana González-Pinto, Josep M. Haro, Nieves López-Fresneña, Alma D. Martínez de Salázar, Juan D. Molina, Rafael M. Ortí-Lucas, Mara Parellada, José Maria Pelayo-Terán, Aurora Pérez-Zapata, José I. Pijoan, Nieves Plana, Maria Teresa Puig, Cristina Rius, Carmen Rodríguez-Blázquez, Ferran Sanz, Consol Serra, Ronald C. Kessler, Ronny Bruffaerts, Eduard Vieta, Víctor Pérez-Solà, MINDCOVID Working group (2020) Revista de psiquiatria y salud mental, S1888-9891(20)30128-2. Advance online publication.
COVID-19 Disease Map, a computational knowledge repository of SARS-CoV-2 virus-host interaction mechanisms
Marek Ostaszewski, Anna Niarakis, Alexander Mazein, Inna Kuperstein, [...], the COVID-19 Disease Map Community
preprint  BioRxiv
DOI: 10.1101/2020.10.26.356014
We describe a large-scale community effort to build an open-access, interoperable, and computable repository of COVID-19 molecular mechanisms - the COVID-19 Disease Map. We discuss the tools, platforms, and guidelines necessary for the distributed development of its contents by a multi-faceted community of biocurators, domain experts, bioinformaticians, and computational biologists. We highlight the role of relevant databases and text mining approaches in enrichment and validation of the curated mechanisms. We describe the contents of the Map and their relevance to the molecular pathophysiology of COVID-19 and the analytical and computational modelling approaches that can be applied for mechanistic data interpretation and predictions. We conclude by demonstrating concrete applications of our work through several use cases and highlight new testable hypotheses.
2021-02-16 2021 other preprint abstract-available data-available 10.1101/2020.10.26.356014 COVID-19 Disease Map, a computational knowledge repository of SARS-CoV-2 virus-host interaction mechanisms Marek Ostaszewski, Anna Niarakis, Alexander Mazein, Inna Kuperstein, Robert Phair, Aurelio Orta-Resendiz, Vidisha Singh, Sara Sadat Aghamiri, Marcio Luis Acencio, Enrico Glaab, Andreas Ruepp, Gisela Fobo, Corinna Montrone, Barbara Brauner, Goar Frishman, Luis Cristóbal Monraz Gómez, Julia Somers, Matti Hoch, Shailendra Kumar Gupta, Julia Scheel, Hanna Borlinghaus, Tobias Czauderna, Falk Schreiber, Arnau Montagud, Miguel Ponce de Leon, Akira Funahashi, Yusuke Hiki, Noriko Hiroi, Takahiro G. Yamada, Andreas Dräger, Alina Renz, Muhammad Naveez, Zsolt Bocskei, Francesco Messina, Daniela Börnigen, Liam Fergusson, Marta Conti, Marius Rameil, Vanessa Nakonecnij, Jakob Vanhoefer, Leonard Schmiester, Muying Wang, Emily E. Ackerman, Jason Shoemaker, Jeremy Zucker, Kristie Oxford, Jeremy Teuton, Ebru Kocakaya, Gökçe Yağmur Summak, Kristina Hanspers, Martina Kutmon, Susan Coort, Lars Eijssen, Friederike Ehrhart, D. A. B. Rex, Denise Slenter, Marvin Martens, Nhung Pham, Robin Haw, Bijay Jassal, Lisa Matthews, Marija Orlic-Milacic, Andrea Senff Ribeiro, Karen Rothfels, Veronica Shamovsky, Ralf Stephan, Cristoffer Sevilla, Thawfeek Varusai, Jean-Marie Ravel, Rupsha Fraser, Vera Ortseifen, Silvia Marchesi, Piotr Gawron, Ewa Smula, Laurent Heirendt, Venkata Satagopam, Guanming Wu, Anders Riutta, Martin Golebiewski, Stuart Owen, Carole Goble, Xiaoming Hu, Rupert W. Overall, Dieter Maier, Angela Bauch, Benjamin M. Gyori, John A. Bachman, Carlos Vega, Valentin Grouès, Miguel Vazquez, Pablo Porras, Luana Licata, Marta Iannuccelli, Francesca Sacco, Anastasia Nesterova, Anton Yuryev, Anita de Waard, Denes Turei, Augustin Luna, Ozgun Babur, Sylvain Soliman, Alberto Valdeolivas, Marina Esteban-Medina, Maria Peña-Chilet, Kinza Rian, Tomáš Helikar, Bhanwar Lal Puniya, Dezso Modos, Agatha Treveil, Marton Olbei, Bertrand De Meulder, Aurélien Dugourd, Aurélien Naldi, Vincent Noël, Laurence Calzone, Chris Sander, Emek Demir, Tamas Korcsmaros, Tom C. Freeman, Franck Augé, Jacques S. Beckmann, Jan Hasenauer, Olaf Wolkenhauer, Egon L. Wilighagen, Alexander R. Pico, Chris T. Evelo, Marc E. Gillespie, Lincoln D. Stein, Henning Hermjakob, Peter D’Eustachio, Julio Saez-Rodriguez, Joaquin Dopazo, Alfonso Valencia, Hiroaki Kitano, Emmanuel Barillot, Charles Auffray, Rudi Balling, Reinhard Schneider, the COVID-19 Disease Map Community BioRxiv
Susceptibility and transmissibility of SARS-CoV-2 variants in transgenic mice expressing the cat angiotensin-converting enzyme 2 (ACE-2) receptor.
Jiménez de Oya N, Calvo-Pinilla E, Mingo-Casas P, Escribano-Romero E, [...], Saiz JC.
One Health. 2024; 18
DOI: 10.1016/j.onehlt.2024.100744
The emergence of SARS-CoV-2 in 2019 and its rapid spread throughout the world has caused the largest pandemic of our modern era. The zoonotic origin of this pathogen highlights the importance of the One Health concept and the need for a coordinated response to this kind of threats. Since its emergence, the virus has caused >7 million deaths worldwide. However, the animal source for human outbreaks remains unknown. The ability of the virus to jump between hosts is facilitated by the presence of the virus receptor, the highly conserved angiotensin-converting enzyme 2 (ACE2), found in various mammals. Positivity for SARS-CoV-2 has been reported in various species, including domestic animals and livestock, but their potential role in bridging viral transmission to humans is still unknown. Additionally, the virus has evolved over the pandemic, resulting in variants with different impacts on human health. Therefore, suitable animal models are crucial to evaluate the susceptibility of different mammalian species to this pathogen and the adaptability of different variants. In this work, we established a transgenic mouse model that expresses the feline ACE2 protein receptor (cACE2) under the human cytokeratin 18 (K18) gene promoter's control, enabling high expression in epithelial cells, which the virus targets. Using this model, we assessed the susceptibility, pathogenicity, and transmission of SARS-CoV-2 variants. Our results show that the sole expression of the cACE2 receptor in these mice makes them susceptible to SARS-CoV-2 variants from the initial pandemic wave but does not enhance susceptibility to omicron variants. Furthermore, we demonstrated efficient contact transmission of SARS-CoV-2 between transgenic mice that express either the feline or the human ACE2 receptor.
2024-04-29 2024 other research-article; Journal Article abstract-available 10.1016/j.onehlt.2024.100744 Susceptibility and transmissibility of SARS-CoV-2 variants in transgenic mice expressing the cat angiotensin-converting enzyme 2 (ACE-2) receptor. Jiménez de Oya N, Calvo-Pinilla E, Mingo-Casas P, Escribano-Romero E, Blázquez AB, Esteban A, Fernández-González R, Pericuesta E, Sánchez-Cordón PJ, Martín-Acebes MA, Gutiérrez-Adán A, Saiz JC. One Health. 2024; 18
Editorial for the Topical Collection "SARS-CoV-2 Infection and COVID-19 Disease".
Martinez-Sobrido L, DeDiego ML.
Pathogens. 2024; 13 (3)
DOI: 10.3390/pathogens13030191
A previously unknown coronavirus, named Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), emerged in the city of Wuhan, China, in December 2019 [...].
2024-02-21 2024 other Editorial abstract-available 10.3390/pathogens13030191 Editorial for the Topical Collection "SARS-CoV-2 Infection and COVID-19 Disease". Martinez-Sobrido L, DeDiego ML. Pathogens. 2024; 13 (3)
Editorial for SARS-CoV-2 and COVID-19 Topical Collection.
Martinez-Sobrido L, Almazán F.
Viruses. 2024; 16 (3)
DOI: 10.3390/v16030356
A previously unknown coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was isolated in Wuhan, China in December 2019, from a patient with a respiratory disease linked to potential contact with wild animals [...].
2024-02-25 2024 other Editorial abstract-available 10.3390/v16030356 Editorial for SARS-CoV-2 and COVID-19 Topical Collection. Martinez-Sobrido L, Almazán F. Viruses. 2024; 16 (3)
Could SARS-CoV-1 Vaccines in the Pipeline Have Contributed to Fighting the COVID-19 Pandemic? Lessons for the Next Coronavirus Plague.
López D, García-Peydró M.
Biomedicines. 2023; 12 (1)
DOI: 10.3390/biomedicines12010062
SARS-CoV-2 caused the devastating COVID-19 pandemic, which, to date, has resulted in more than 800 million confirmed cases and 7 million deaths worldwide. The rapid development and distribution (at least in high-income countries) of various vaccines prevented these overwhelming numbers of infections and deaths from being much higher. But would it have been possible to develop a prophylaxis against this pandemic more quickly? Since SARS-CoV-2 belongs to the subgenus sarbecovirus, with its highly homologous SARS-CoV-1, we propose here that while SARS-CoV-2-specific vaccines are being developed, phase II clinical trials of specific SARS-CoV-1 vaccines, which have been in the pipeline since the early 20th century, could have been conducted to test a highly probable cross-protection between SARS-CoV-1 and SARS-CoV-2.
2023-12-27 2023 other other; Journal Article abstract-available 10.3390/biomedicines12010062 Could SARS-CoV-1 Vaccines in the Pipeline Have Contributed to Fighting the COVID-19 Pandemic? Lessons for the Next Coronavirus Plague. López D, García-Peydró M. Biomedicines. 2023; 12 (1)
SCARF Genes in COVID-19 and Kidney Disease: A Path to Comorbidity-Specific Therapies
Carriazo S, Abasheva D, Duarte D, Ortiz A, [...], Sanchez-Niño M.
Int J Mol Sci. 2023; 24 (22)
DOI:
2023-11-01 2023 other review-article; Review; Journal Article SCARF Genes in COVID-19 and Kidney Disease: A Path to Comorbidity-Specific Therapies Carriazo S, Abasheva D, Duarte D, Ortiz A, Sanchez-Niño M. Int J Mol Sci. 2023; 24 (22)
A Comparison between SARS-CoV-2 and Gram-Negative Bacteria-Induced Hyperinflammation and Sepsis.
Brandenburg K, Ferrer-Espada R, Martinez-de-Tejada G, Nehls C, [...], Garidel P.
Int J Mol Sci. 2023; 24 (20)
DOI: 10.3390/ijms242015169
Sepsis is a life-threatening condition caused by the body's overwhelming response to an infection, such as pneumonia or urinary tract infection. It occurs when the immune system releases cytokines into the bloodstream, triggering widespread inflammation. If not treated, it can lead to organ failure and death. Unfortunately, sepsis has a high mortality rate, with studies reporting rates ranging from 20% to over 50%, depending on the severity and promptness of treatment. According to the World Health Organization (WHO), the annual death toll in the world is about 11 million. One of the main toxins responsible for inflammation induction are lipopolysaccharides (LPS, endotoxin) from Gram-negative bacteria, which rank among the most potent immunostimulants found in nature. Antibiotics are consistently prescribed as a part of anti-sepsis-therapy. However, antibiotic therapy (i) is increasingly ineffective due to resistance development and (ii) most antibiotics are unable to bind and neutralize LPS, a prerequisite to inhibit the interaction of endotoxin with its cellular receptor complex, namely Toll-like receptor 4 (TLR4)/MD-2, responsible for the intracellular cascade leading to pro-inflammatory cytokine secretion. The pandemic virus SARS-CoV-2 has infected hundreds of millions of humans worldwide since its emergence in 2019. The COVID-19 (Coronavirus disease-19) caused by this virus is associated with high lethality, particularly for elderly and immunocompromised people. As of August 2023, nearly 7 million deaths were reported worldwide due to this disease. According to some reported studies, upregulation of TLR4 and the subsequent inflammatory signaling detected in COVID-19 patients "mimics bacterial sepsis". Furthermore, the immune response to SARS-CoV-2 was described by others as "mirror image of sepsis". Similarly, the cytokine profile in sera from severe COVID-19 patients was very similar to those suffering from the acute respiratory distress syndrome (ARDS) and sepsis. Finally, the severe COVID-19 infection is frequently accompanied by bacterial co-infections, as well as by the presence of significant LPS concentrations. In the present review, we will analyze similarities and differences between COVID-19 and sepsis at the pathophysiological, epidemiological, and molecular levels.
2023-10-14 2023 other review-article; Review; Journal Article abstract-available 10.3390/ijms242015169 A Comparison between SARS-CoV-2 and Gram-Negative Bacteria-Induced Hyperinflammation and Sepsis. Brandenburg K, Ferrer-Espada R, Martinez-de-Tejada G, Nehls C, Fukuoka S, Mauss K, Weindl G, Garidel P. Int J Mol Sci. 2023; 24 (20)
SARS-CoV-2 S protein activates NLRP3 inflammasome and deregulates coagulation factors in endothelial and immune cells.
Villacampa A, Alfaro E, Morales C, Díaz-García E, [...], Peiró C.
Cell Commun Signal. 2024; 22 (1)
DOI: 10.1186/s12964-023-01397-6

Background

Hyperinflammation, hypercoagulation and endothelial injury are major findings in acute and post-COVID-19. The SARS-CoV-2 S protein has been detected as an isolated element in human tissues reservoirs and is the main product of mRNA COVID-19 vaccines. We investigated whether the S protein alone triggers pro-inflammatory and pro-coagulant responses in primary cultures of two cell types deeply affected by SARS-CoV-2, such are monocytes and endothelial cells.

Methods

In human umbilical vein endothelial cells (HUVEC) and monocytes, the components of NF-κB and the NLRP3 inflammasome system, as well as coagulation regulators, were assessed by qRT-PCR, Western blot, flow cytometry, or indirect immunofluorescence.

Results

S protein activated NF-κB, promoted pro-inflammatory cytokines release, and triggered the priming and activation of the NLRP3 inflammasome system resulting in mature IL-1β formation in both cell types. This was paralleled by enhanced production of coagulation factors such as von Willebrand factor (vWF), factor VIII or tissue factor, that was mediated, at least in part, by IL-1β. Additionally, S protein failed to enhance ADAMTS-13 levels to counteract the pro-coagulant activity of vWF multimers. Monocytes and HUVEC barely expressed angiotensin-converting enzyme-2. Pharmacological approaches and gene silencing showed that TLR4 receptors mediated the effects of S protein in monocytes, but not in HUVEC.

Conclusion

S protein behaves both as a pro-inflammatory and pro-coagulant stimulus in human monocytes and endothelial cells. Interfering with the receptors or signaling pathways evoked by the S protein may help preventing immune and vascular complications driven by such an isolated viral element. Video Abstract.
2024-01-15 2024 other Video-Audio Media; Research Support, Non-U.S. Gov't; research-article; Journal Article abstract-available 10.1186/s12964-023-01397-6 SARS-CoV-2 S protein activates NLRP3 inflammasome and deregulates coagulation factors in endothelial and immune cells. Villacampa A, Alfaro E, Morales C, Díaz-García E, López-Fernández C, Bartha JL, López-Sánchez F, Lorenzo Ó, Moncada S, Sánchez-Ferrer CF, García-Río F, Cubillos-Zapata C, Peiró C. Cell Commun Signal. 2024; 22 (1)
CompCorona: A web application for comparative transcriptome analyses of coronaviruses reveals SARS-CoV-2-specific host response.
Salihoğlu R, Saraçoğlu F, Sibai M, Zengin T, [...], Süzek T.
Turk J Biol. 2023; 47 (6)
DOI: 10.55730/1300-0152.2673

Background/aim

Understanding the mechanism of host transcriptomic response to infection by the SARS-CoV-2 virus is crucial, especially for patients suffering from long-term effects of COVID-19, such as long COVID or pericarditis inflammation, potentially linked to side effects of the SARS-CoV-2 spike proteins. We conducted comprehensive transcriptome and enrichment analyses on lung and peripheral blood mononuclear cells (PBMCs) infected with SARS-CoV-2, as well as on SARS-CoV and MERS-CoV, to uncover shared pathways and elucidate their common disease progression and viral replication mechanisms.

Materials and methods

We developed CompCorona, the first interactive online tool for visualizing gene response variance among the family Coronaviridae through 2D and 3D principal component analysis (PCA) and exploring systems biology variance using pathway plots. We also made preprocessed datasets of lungs and PBMCs infected by SARS-CoV-2, SARS-CoV, and MERS-CoV publicly available through CompCorona.

Results

One remarkable finding from the lung and PBMC datasets for infections by SARS-CoV-2, but not infections by other coronaviruses (CoVs), was the significant downregulation of the angiogenin (ANG) and vascular endothelial growth factor A (VEGFA) genes, both directly involved in epithelial and vascular endothelial cell dysfunction. Suppression of the TNF signaling pathway was also observed in cells infected by SARS-CoV-2, along with simultaneous activation of complement and coagulation cascades and pertussis pathways. The ribosome pathway was found to be universally suppressed across all three viruses. The CompCorona online tool enabled the comparative analysis of 9 preprocessed host transcriptome datasets of cells infected by CoVs, revealing the specific host response differences in cases of SARS-CoV-2 infection. This included identifying markers of epithelial dysfunction via interactive 2D and 3D PCA, Venn diagrams, and pathway plots.

Conclusion

Our findings suggest that infection by SARS-CoV-2 might induce pulmonary epithelial dysfunction, a phenomenon not observed in cells infected by other CoVs. The publicly available CompCorona tool, along with the preprocessed datasets of cells infected by various CoVs, constitutes a valuable resource for further research into CoV-associated syndromes.
2023-12-15 2023 other research-article; Journal Article abstract-available 10.55730/1300-0152.2673 CompCorona: A web application for comparative transcriptome analyses of coronaviruses reveals SARS-CoV-2-specific host response. Salihoğlu R, Saraçoğlu F, Sibai M, Zengin T, Abak Masud B, Karasoy O, Süzek T. Turk J Biol. 2023; 47 (6)
SARS-CoV-2 remodels the landscape of small non-coding RNAs with infection time and symptom severity.
Corell-Sierra J, Marquez-Molins J, Marqués MC, Hernandez-Azurdia AG, [...], Gómez G.
NPJ Syst Biol Appl. 2024; 10 (1)
DOI: 10.1038/s41540-024-00367-z
The COVID-19 pandemic caused by the coronavirus SARS-CoV-2 has significantly impacted global health, stressing the necessity of basic understanding of the host response to this viral infection. In this study, we investigated how SARS-CoV-2 remodels the landscape of small non-coding RNAs (sncRNA) from a large collection of nasopharyngeal swab samples taken at various time points from patients with distinct symptom severity. High-throughput RNA sequencing analysis revealed a global alteration of the sncRNA landscape, with abundance peaks related to species of 21-23 and 32-33 nucleotides. Host-derived sncRNAs, including microRNAs (miRNAs), transfer RNA-derived small RNAs (tsRNAs), and small nucleolar RNA-derived small RNAs (sdRNAs) exhibited significant differential expression in infected patients compared to controls. Importantly, miRNA expression was predominantly down-regulated in response to SARS-CoV-2 infection, especially in patients with severe symptoms. Furthermore, we identified specific tsRNAs derived from Glu- and Gly-tRNAs as major altered elements upon infection, with 5' tRNA halves being the most abundant species and suggesting their potential as biomarkers for viral presence and disease severity prediction. Additionally, down-regulation of C/D-box sdRNAs and altered expression of tinyRNAs (tyRNAs) were observed in infected patients. These findings provide valuable insights into the host sncRNA response to SARS-CoV-2 infection and may contribute to the development of further diagnostic and therapeutic strategies in the clinic.
2024-04-17 2024 other research-article; Journal Article abstract-available 10.1038/s41540-024-00367-z SARS-CoV-2 remodels the landscape of small non-coding RNAs with infection time and symptom severity. Corell-Sierra J, Marquez-Molins J, Marqués MC, Hernandez-Azurdia AG, Montagud-Martínez R, Cebriá-Mendoza M, Cuevas JM, Albert E, Navarro D, Rodrigo G, Gómez G. NPJ Syst Biol Appl. 2024; 10 (1)
Immunization with V987H-stabilized Spike glycoprotein protects K18-hACE2 mice and golden Syrian hamsters upon SARS-CoV-2 infection.
Ávila-Nieto C, Vergara-Alert J, Amengual-Rigo P, Ainsua-Enrich E, [...], Carrillo J.
Nat Commun. 2024; 15 (1)
DOI: 10.1038/s41467-024-46714-w
Safe and effective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are crucial to fight against the coronavirus disease 2019 pandemic. Most vaccines are based on a mutated version of the Spike glycoprotein [K986P/V987P (S-2P)] with improved stability, yield and immunogenicity. However, S-2P is still produced at low levels. Here, we describe the V987H mutation that increases by two-fold the production of the recombinant Spike and the exposure of the receptor binding domain (RBD). S-V987H immunogenicity is similar to S-2P in mice and golden Syrian hamsters (GSH), and superior to a monomeric RBD. S-V987H immunization confer full protection against severe disease in K18-hACE2 mice and GSH upon SARS-CoV-2 challenge (D614G or B.1.351 variants). Furthermore, S-V987H immunized K18-hACE2 mice show a faster tissue viral clearance than RBD- or S-2P-vaccinated animals challenged with D614G, B.1.351 or Omicron BQ1.1 variants. Thus, S-V987H protein might be considered for future SARS-CoV-2 vaccines development.
2024-03-21 2024 other research-article; Journal Article abstract-available 10.1038/s41467-024-46714-w Immunization with V987H-stabilized Spike glycoprotein protects K18-hACE2 mice and golden Syrian hamsters upon SARS-CoV-2 infection. Ávila-Nieto C, Vergara-Alert J, Amengual-Rigo P, Ainsua-Enrich E, Brustolin M, Rodríguez de la Concepción ML, Pedreño-Lopez N, Rodon J, Urrea V, Pradenas E, Marfil S, Ballana E, Riveira-Muñoz E, Pérez M, Roca N, Tarrés-Freixas F, Cantero G, Pons-Grífols A, Rovirosa C, Aguilar-Gurrieri C, Ortiz R, Barajas A, Trinité B, Lepore R, Muñoz-Basagoiti J, Perez-Zsolt D, Izquierdo-Useros N, Valencia A, Blanco J, Guallar V, Clotet B, Segalés J, Carrillo J. Nat Commun. 2024; 15 (1)
Marine-Derived Bioactive Metabolites as a Potential Therapeutic Intervention in Managing Viral Diseases: Insights from the SARS-CoV-2 In Silico and Pre-Clinical Studies.
Okechukwu QN, Adepoju FO, Kanwugu ON, Adadi P, [...], Okpala COR.
Pharmaceuticals (Basel). 2024; 17 (3)
DOI: 10.3390/ph17030328
Worldwide urbanization and subsequent migration have accelerated the emergence and spread of diverse novel human diseases. Among them, diseases caused by viruses could result in epidemics, typified by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which hit the globe towards the end of December 2019. The global battle against SARS-CoV-2 has reignited interest in finding alternative treatments for viral infections. The marine world offers a large repository of diverse and unique bioactive compounds. Over the years, many antiviral compounds from marine organisms have been isolated and tested in vitro and in vivo. However, given the increasing need for alternative treatment, in silico analysis appears to provide a time- and cost-effective approach to identifying the potential antiviral compounds from the vast pool of natural metabolites isolated from marine organisms. In this perspective review, we discuss marine-derived bioactive metabolites as potential therapeutics for all known disease-causing viruses including the SARS-CoV-2. We demonstrate the efficacy of marine-derived bioactive metabolites in the context of various antiviral activities and their in silico, in vitro, and in vivo capacities.
2024-03-01 2024 other review-article; Review; Journal Article abstract-available 10.3390/ph17030328 Marine-Derived Bioactive Metabolites as a Potential Therapeutic Intervention in Managing Viral Diseases: Insights from the SARS-CoV-2 In Silico and Pre-Clinical Studies. Okechukwu QN, Adepoju FO, Kanwugu ON, Adadi P, Serrano-Aroca Á, Uversky VN, Okpala COR. Pharmaceuticals (Basel). 2024; 17 (3)
The role of colchicine in the management of COVID-19: a Meta-analysis.
Elshiwy K, Amin GEE, Farres MN, Samir R, [...], Allam MF.
BMC Pulm Med. 2024; 24 (1)
DOI: 10.1186/s12890-024-03001-0

Background

The Coronavirus disease 2019 (COVID-19) pandemic has robustly affected the global healthcare and economic systems and it was caused by coronavirus-2 (SARS-CoV-2). The clinical presentation of the disease ranges from a flu-like illness to severe pneumonia and death. Till September 2022, the cumulative number of cases exceeded 600 million worldwide and deaths were more than 6 million. Colchicine is an alkaloid drug that is used in many autoinflammatory conditions e.g., gout, familial Mediterranean fever, and Behçet's syndrome. Colchicine inhibits the production of superoxide and the release of interleukins that stimulate the inflammatory cascade. Colchicine decreases the differentiation of myofibroblast and the release of fibrotic mediators including transforming growth factor (TGF-β1) that are related to the fibrosis. Moreover, colchicine has been used to traet viral myocarditis caused by CMV or EBV, interstitial pneumonia, and pericarditis resulting from influenza B infection. Additionally, colchicine is considered safe and affordable with wide availability.

Objective

The aim of the current study was to assess the evidence of colchicine effectiveness in COVID-19 treatment.

Methods

A comprehensive review of the literature was done till May 2022 and yielded 814 articles after ranking the articles according to authors and year of publication. Only 8 clinical trials and cohort studies fulfilling the inclusion criteria were included for further steps of data collection, analysis, and reporting.

Results

This meta-analysis involved 16,488 patients; 8146 patients in the treatment group and 8342 patients in the control group. The results showed that colchicine resulted in a significant reduction in the mortality rate among patients received colchicine in comparison with placebo or standard care (RR 0.35, 95%CI: 0.15-0.79). Colchicine resulted in a significant decrease in the need for O2 therapy in patients with COVID-19 (RR 0.07, 95%CI 0.02-0.27, P = 0.000024). However, colchicine had no significant effect on the following outcomes among COVID-19 patients: the need for hospitalization, ICU admission, artificial ventilation, and hospital discharge rate. Among the PCR confirmed COVID-19 patients, colchicine decreased the hospitalization rate (RR 0.75, 95%CI 0.57-0.99, P = 0.042). However, colchicine had no effect on mortality and the need for mechanical ventilation among this subgroup.

Conclusion

Colchicine caused a significant clinical improvement among COVID-19 patients as compared with the standard care or placebo, in terms of the need for O2, and mortality. This beneficial effect could play a role in the management of COVID-19 especially severe cases to decrease need for oxygen and to decrease mortality among these patients.
2024-04-20 2024 other Meta-Analysis; research-article; Review; Journal Article abstract-available 10.1186/s12890-024-03001-0 The role of colchicine in the management of COVID-19: a Meta-analysis. Elshiwy K, Amin GEE, Farres MN, Samir R, Allam MF. BMC Pulm Med. 2024; 24 (1)
Multiple Lines of Evidence Support 199 SARS-CoV-2 Positively Selected Amino Acid Sites.
Ferreira P, Soares R, López-Fernández H, Vazquez N, [...], Vieira J.
Int J Mol Sci. 2024; 25 (4)
DOI: 10.3390/ijms25042428
SARS-CoV-2 amino acid variants that contribute to an increased transmissibility or to host immune system escape are likely to increase in frequency due to positive selection and may be identified using different methods, such as codeML, FEL, FUBAR, and MEME. Nevertheless, when using different methods, the results do not always agree. The sampling scheme used in different studies may partially explain the differences that are found, but there is also the possibility that some of the identified positively selected amino acid sites are false positives. This is especially important in the context of very large-scale projects where hundreds of analyses have been performed for the same protein-coding gene. To account for these issues, in this work, we have identified positively selected amino acid sites in SARS-CoV-2 and 15 other coronavirus species, using both codeML and FUBAR, and compared the location of such sites in the different species. Moreover, we also compared our results to those that are available in the COV2Var database and the frequency of the 10 most frequent variants and predicted protein location to identify those sites that are supported by multiple lines of evidence. Amino acid changes observed at these sites should always be of concern. The information reported for SARS-CoV-2 can also be used to identify variants of concern in other coronaviruses.
2024-02-19 2024 other research-article; Journal Article abstract-available 10.3390/ijms25042428 Multiple Lines of Evidence Support 199 SARS-CoV-2 Positively Selected Amino Acid Sites. Ferreira P, Soares R, López-Fernández H, Vazquez N, Reboiro-Jato M, Vieira CP, Vieira J. Int J Mol Sci. 2024; 25 (4)
Coronavirus disease 2019 and lung cancer: where are we?
Ocanto A, Mielgo-Rubio X, Luna Tirado J, Linares Mesa N, [...], Couñago F.
Explor Target Antitumor Ther. 2023; 4 (5)
DOI: 10.37349/etat.2023.00182
Oncology patients are more susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection due to hospital contact and an immunological system that can be compromised by antineoplastic therapy and supportive treatments. Certain similarities have been described in the physiopathology of coronavirus disease 2019 (COVID-19) and lung cancer (LC) that may explain the higher probability of these patients of developing a more serious disease with more frequent hospitalizations and even death, especially with the addition of smoking, cardiovascular and respiratory comorbidities, old age and corticosteroids use. Pre-existing lesions and cancer therapies change the normal architecture of the lungs, so diagnostic scales such as COVID-19 Reporting and Data System (CO-RADS) are of vital importance for a correct diagnosis and patient homogenization, with a high inter-observer correlation. Moreover, anticancer treatments have required an adaptation to reduce the number of visits to the hospital [hypofractionated radiotherapy (RT), larger intervals between chemotherapy cycles, delay in follow-up tests, among others]. In a way, this has also caused a delay in the diagnosis of new cancers. On the other hand, vaccination has had a positive impact on the mortality of these patients, who maintain a similar seroprevalence to the rest of the population, with a similar impact in mortality.
2023-10-30 2023 other review-article; Review; Journal Article abstract-available 10.37349/etat.2023.00182 Coronavirus disease 2019 and lung cancer: where are we? Ocanto A, Mielgo-Rubio X, Luna Tirado J, Linares Mesa N, López Valcárcel M, Pedraza S, Barragan VV, Nieto PV, Martín JZ, Couñago F. Explor Target Antitumor Ther. 2023; 4 (5)
The Role of Heparin in Postural Orthostatic Tachycardia Syndrome and Other Post-Acute Sequelae of COVID-19.
Gómez-Moyano E, Pavón-Morón J, Rodríguez-Capitán J, Bardán-Rebollar D, [...], Pérez-Belmonte LM.
J Clin Med. 2024; 13 (8)
DOI: 10.3390/jcm13082405
The therapeutic management and short-term consequences of the coronavirus disease 2019 (COVID-19) are well known. However, COVID-19 post-acute sequelae are less known and represent a public health problem worldwide. Patients with COVID-19 who present post-acute sequelae may display immune dysregulation, a procoagulant state, and persistent microvascular endotheliopathy that could trigger microvascular thrombosis. These elements have also been implicated in the physiopathology of postural orthostatic tachycardia syndrome, a frequent sequela in post-COVID-19 patients. These mechanisms, directly associated with post-acute sequelae, might determine the thrombotic consequences of COVID-19 and the need for early anticoagulation therapy. In this context, heparin has several potential benefits, including immunomodulatory, anticoagulant, antiviral, pro-endothelial, and vascular effects, that could be helpful in the treatment of COVID-19 post-acute sequelae. In this article, we review the evidence surrounding the post-acute sequelae of COVID-19 and the potential benefits of the use of heparin, with a special focus on the treatment of postural orthostatic tachycardia syndrome.
2024-04-20 2024 other review-article; Review; Journal Article abstract-available 10.3390/jcm13082405 The Role of Heparin in Postural Orthostatic Tachycardia Syndrome and Other Post-Acute Sequelae of COVID-19. Gómez-Moyano E, Pavón-Morón J, Rodríguez-Capitán J, Bardán-Rebollar D, Ramos-Carrera T, Villalobos-Sánchez A, Pérez de Pedro I, Ruiz-García FJ, Mora-Robles J, López-Sampalo A, Pérez-Velasco MA, Bernal-López MR, Gómez-Huelgas R, Jiménez-Navarro M, Romero-Cuevas M, Costa F, Trenas A, Pérez-Belmonte LM. J Clin Med. 2024; 13 (8)
The Immune Response of OAS1, IRF9, and IFI6 Genes in the Pathogenesis of COVID-19.
Gajate-Arenas M, Fricke-Galindo I, García-Pérez O, Domínguez-de-Barros A, [...], Córdoba-Lanús E.
Int J Mol Sci. 2024; 25 (9)
DOI: 10.3390/ijms25094632
COVID-19 is characterized by a wide range of clinical manifestations, where aging, underlying diseases, and genetic background are related to worse outcomes. In the present study, the differential expression of seven genes related to immunity, IRF9, CCL5, IFI6, TGFB1, IL1B, OAS1, and TFRC, was analyzed in individuals with COVID-19 diagnoses of different disease severities. Two-step RT-qPCR was performed to determine the relative gene expression in whole-blood samples from 160 individuals. The expression of OAS1 (p < 0.05) and IFI6 (p < 0.05) was higher in moderate hospitalized cases than in severe ones. Increased gene expression of OAS1 (OR = 0.64, CI = 0.52-0.79; p = 0.001), IRF9 (OR = 0.581, CI = 0.43-0.79; p = 0.001), and IFI6 (OR = 0.544, CI = 0.39-0.69; p < 0.001) was associated with a lower risk of requiring IMV. Moreover, TGFB1 (OR = 0.646, CI = 0.50-0.83; p = 0.001), CCL5 (OR = 0.57, CI = 0.39-0.83; p = 0.003), IRF9 (OR = 0.80, CI = 0.653-0.979; p = 0.03), and IFI6 (OR = 0.827, CI = 0.69-0.991; p = 0.039) expression was associated with patient survival. In conclusion, the relevance of OAS1, IRF9, and IFI6 in controlling the viral infection was confirmed.
2024-04-24 2024 other research-article; Journal Article abstract-available 10.3390/ijms25094632 The Immune Response of <i>OAS1</i>, <i>IRF9</i>, and <i>IFI6</i> Genes in the Pathogenesis of COVID-19. Gajate-Arenas M, Fricke-Galindo I, García-Pérez O, Domínguez-de-Barros A, Pérez-Rubio G, Dorta-Guerra R, Buendía-Roldán I, Chávez-Galán L, Lorenzo-Morales J, Falfán-Valencia R, Córdoba-Lanús E. Int J Mol Sci. 2024; 25 (9)
Pancreatic and Hepatic Injury in COVID-19: A Worse Prognosis in NAFLD Patients?
Mengual-Moreno E, Nava M, Manzano A, Ariza D, [...], Bermúdez V.
Biomedicines. 2024; 12 (2)
DOI: 10.3390/biomedicines12020283
The novel disease produced by SARS-CoV-2 mainly harms the respiratory tract, but it has shown the capacity to affect multiple organs. Epidemiologic evidence supports the relationship between Coronavirus Disease 2019 (COVID-19) and pancreatic and hepatic injury development, identified by alterations in these organ function markers. In this regard, it is important to ascertain how the current prevalence of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) might affect COVID-19 evolution and complications. Although it is not clear how SARS-CoV-2 affects both the pancreas and the liver, a multiplicity of potential pathophysiological mechanisms seem to be implicated; among them, a direct viral-induced injury to the organ involving liver and pancreas ACE2 expression. Additionally, immune system dysregulation, coagulopathies, and drugs used to treat the disease could be key for developing complications associated with the patient's clinical decline. This review aims to provide an overview of the available epidemiologic evidence regarding developing liver and pancreatic alterations in patients with COVID-19, as well as the possible role that NAFLD/NASH might play in the pathophysiological mechanisms underlying some of the complications associated with COVID-19. This review employed a comprehensive search on PubMed using relevant keywords and filters. From the initial 126 articles, those aligning with the research target were selected and evaluated for their methodologies, findings, and conclusions. It sheds light on the potential pathophysiological mechanisms underlying this relationship. As a result, it emphasises the importance of monitoring pancreatic and hepatic function in individuals affected by COVID-19.
2024-01-26 2024 other review-article; Review; Journal Article abstract-available 10.3390/biomedicines12020283 Pancreatic and Hepatic Injury in COVID-19: A Worse Prognosis in NAFLD Patients? Mengual-Moreno E, Nava M, Manzano A, Ariza D, D'Marco L, Castro A, Marquina MA, Hernández M, Corredor-Pereira C, Checa-Ros A, Bermúdez V. Biomedicines. 2024; 12 (2)
Protein Quality Control Systems and ER Stress as Key Players in SARS-CoV-2-Induced Neurodegeneration.
Gavilán E, Medina-Guzman R, Bahatyrevich-Kharitonik B, Ruano D.
Cells. 2024; 13 (2)
DOI: 10.3390/cells13020123
The COVID-19 pandemic has brought to the forefront the intricate relationship between SARS-CoV-2 and its impact on neurological complications, including potential links to neurodegenerative processes, characterized by a dysfunction of the protein quality control systems and ER stress. This review article explores the role of protein quality control systems, such as the Unfolded Protein Response (UPR), the Endoplasmic Reticulum-Associated Degradation (ERAD), the Ubiquitin-Proteasome System (UPS), autophagy and the molecular chaperones, in SARS-CoV-2 infection. Our hypothesis suggests that SARS-CoV-2 produces ER stress and exploits the protein quality control systems, leading to a disruption in proteostasis that cannot be solved by the host cell. This disruption culminates in cell death and may represent a link between SARS-CoV-2 and neurodegeneration.
2024-01-09 2024 other Research Support, Non-U.S. Gov't; review-article; Review; Journal Article abstract-available 10.3390/cells13020123 Protein Quality Control Systems and ER Stress as Key Players in SARS-CoV-2-Induced Neurodegeneration. Gavilán E, Medina-Guzman R, Bahatyrevich-Kharitonik B, Ruano D. Cells. 2024; 13 (2)
Cell type dependent stability and virulence of a recombinant SARS-CoV-2, and engineering of a propagation deficient RNA replicon to analyze virus RNA synthesis.
Wang L, Guzman M, Muñoz-Santos D, Honrubia JM, [...], Zuñiga S.
Front Cell Infect Microbiol. 2023; 13
DOI: 10.3389/fcimb.2023.1268227
Engineering of reverse genetics systems for newly emerged viruses allows viral genome manipulation, being an essential tool for the study of virus life cycle, virus-host interactions and pathogenesis, as well as for the development of effective antiviral strategies. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an emergent human coronavirus that has caused the coronavirus disease (COVID-19) pandemic. The engineering of a full-length infectious cDNA clone and a fluorescent replicon of SARS-CoV-2 Wuhan-Hu-1, using a bacterial artificial chromosome, is reported. Viral growth and genetic stability in eleven cell lines were analyzed, showing that both VeroE6 cells overexpressing transmembrane serin protease 2 (TMPRSS2) and human lung derived cells resulted in the optimization of a cell system to preserve SARS-CoV-2 genetic stability. The recombinant SARS-CoV-2 virus and a point mutant expressing the D614G spike protein variant were virulent in a mouse model. The RNA replicon was propagation-defective, allowing its use in BSL-2 conditions to analyze viral RNA synthesis. The SARS-CoV-2 reverse genetics systems developed constitute a useful tool for studying the molecular biology of the virus, the development of genetically defined vaccines and to establish systems for antiviral compounds screening.
2023-10-24 2023 other Research Support, Non-U.S. Gov't; research-article; Journal Article abstract-available 10.3389/fcimb.2023.1268227 Cell type dependent stability and virulence of a recombinant SARS-CoV-2, and engineering of a propagation deficient RNA replicon to analyze virus RNA synthesis. Wang L, Guzman M, Muñoz-Santos D, Honrubia JM, Ripoll-Gomez J, Delgado R, Sola I, Enjuanes L, Zuñiga S. Front Cell Infect Microbiol. 2023; 13
The inflammatory spectrum of cardiomyopathies.
Musigk N, Suwalski P, Golpour A, Fairweather D, [...], Heidecker B.
Front Cardiovasc Med. 2024; 11
DOI: 10.3389/fcvm.2024.1251780
Infiltration of the myocardium with various cell types, cytokines and chemokines plays a crucial role in the pathogenesis of cardiomyopathies including inflammatory cardiomyopathies and myocarditis. A more comprehensive understanding of the precise immune mechanisms involved in acute and chronic myocarditis is essential to develop novel therapeutic approaches. This review offers a comprehensive overview of the current knowledge of the immune landscape in cardiomyopathies based on etiology. It identifies gaps in our knowledge about cardiac inflammation and emphasizes the need for new translational approaches to improve our understanding thus enabling development of novel early detection methods and more effective treatments.
2024-02-23 2024 other review-article; Review; Journal Article abstract-available 10.3389/fcvm.2024.1251780 The inflammatory spectrum of cardiomyopathies. Musigk N, Suwalski P, Golpour A, Fairweather D, Klingel K, Martin P, Frustaci A, Cooper LT, Lüscher TF, Landmesser U, Heidecker B. Front Cardiovasc Med. 2024; 11
Long-Term Radiological Pulmonary Changes in Mechanically Ventilated Patients with Respiratory Failure due to SARS-CoV-2 Infection.
Stoian M, Roman A, Boeriu A, Onișor D, [...], Stoian A.
Biomedicines. 2023; 11 (10)
DOI: 10.3390/biomedicines11102637
From the first reports of SARS-CoV-2, at the end of 2019 to the present, the global mortality associated with COVID-19 has reached 6,952,522 deaths as reported by the World Health Organization (WHO). Early intubation and mechanical ventilation can increase the survival rate of critically ill patients. This prospective study was carried out on 885 patients in the ICU of Mureș County Clinical Hospital, Romania. After applying inclusion and exclusion criteria, a total of 54 patients were included. Patients were monitored during hospitalization and at 6-month follow-up. We analyzed the relationship between invasive mechanical ventilation (IMV) and non-invasive mechanical ventilation (NIMV) and radiological changes on thoracic CT scans performed at 6-month follow-up and found no significant association. Regarding paraclinical analysis, there was a statistically significant association between patients grouped by IMV and ferritin level on day 1 of admission (p = 0.034), and between patients grouped by PaO2/FiO2 ratio with metabolic syndrome (p = 0.03) and the level of procalcitonin (p = 0.01). A significant proportion of patients with COVID-19 admitted to the ICU developed pulmonary fibrosis as observed at a 6-month evaluation. Patients with oxygen supplementation or mechanical ventilation require dynamic monitoring and radiological investigations, as there is a possibility of long-term pulmonary fibrosis that requires pharmacological interventions and finding new therapeutic alternatives.
2023-09-26 2023 other research-article; Journal Article abstract-available 10.3390/biomedicines11102637 Long-Term Radiological Pulmonary Changes in Mechanically Ventilated Patients with Respiratory Failure due to SARS-CoV-2 Infection. Stoian M, Roman A, Boeriu A, Onișor D, Bandila SR, Babă DF, Cocuz I, Niculescu R, Costan A, Laszlo SȘ, Corău D, Stoian A. Biomedicines. 2023; 11 (10)
Differential expression of antiviral and immune-related genes in individuals with COVID-19 asymptomatic or with mild symptoms.
Gajate-Arenas M, García-Pérez O, Chao-Pellicer J, Domínguez-De-Barros A, [...], Córdoba-Lanus E.
Front Cell Infect Microbiol. 2023; 13
DOI: 10.3389/fcimb.2023.1173213
COVID-19 is characterized by a wide range of symptoms where the genetic background plays a key role in SARS-CoV-2 infection. In this study, the relative expression of IRF9, CCL5, IFI6, TGFB1, IL1B, OAS1, and TFRC genes (related to immunity and antiviral activity) was analyzed in upper airway samples from 127 individuals (97 COVID-19 positive and 30 controls) by using a two-step RT-PCR. All genes excepting IL1B (p=0.878) showed a significantly higher expression (p<0.005) in COVID-19 cases than in the samples from the control group suggesting that in asymptomatic-mild cases antiviral and immune system cells recruitment gene expression is being promoted. Moreover, IFI6 (p=0.002) and OAS1 (p=0.044) were upregulated in cases with high viral loads, which could be related to protection against severe forms of this viral infection. In addition, a higher frequency (68.7%) of individuals infected with the Omicron variant presented higher viral load values of infection when compared to individuals infected with other variants (p<0.001). Furthermore, an increased expression of IRF9 (p<0.001), IFI6 (p<0.001), OAS1 (p=0.011), CCL5, (p=0.003) and TGFB1 (p<0.001) genes was observed in individuals infected with SARS-CoV-2 wildtype virus, which might be due to immune response evasion of the viral variants and/or vaccination. The obtained results indicate a protective role of IFI6, OAS1 and IRF9 in asymptomatic -mild cases of SARS-CoV-2 infection while the role of TGFB1 and CCL5 in the pathogenesis of the disease is still unclear. The importance of studying the dysregulation of immune genes in relation to the infective variant is stand out in this study.
2023-06-14 2023 other brief-report; Research Support, Non-U.S. Gov't; Journal Article abstract-available 10.3389/fcimb.2023.1173213 Differential expression of antiviral and immune-related genes in individuals with COVID-19 asymptomatic or with mild symptoms. Gajate-Arenas M, García-Pérez O, Chao-Pellicer J, Domínguez-De-Barros A, Dorta-Guerra R, Lorenzo-Morales J, Córdoba-Lanus E. Front Cell Infect Microbiol. 2023; 13
Understanding the neurological implications of acute and long COVID using brain organoids.
García-González L, Martí-Sarrias A, Puertas MC, Bayón-Gil Á, [...], Acosta S.
Dis Model Mech. 2023; 16 (7)
DOI: 10.1242/dmm.050049
As early as in the acute phase of the coronavirus disease 2019 (COVID-19) pandemic, the research community voiced concerns about the long-term implications of infection. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), like many other viruses, can trigger chronic disorders that last months or even years. Long COVID, the chronic and persistent disorder lasting more than 12 weeks after the primary infection with SARS-CoV-2, involves a variable number of neurological manifestations, ranging from mild to severe and even fatal. In vitro and in vivo modeling suggest that SARS-CoV-2 infection drives changes within neurons, glia and the brain vasculature. In this Review, we summarize the current understanding of the neuropathology of acute and long COVID, with particular emphasis on the knowledge derived from brain organoid models. We highlight the advantages and main limitations of brain organoids, leveraging their human-derived origin, their similarity in cellular and tissue architecture to human tissues, and their potential to decipher the pathophysiology of long COVID.
2023-07-17 2023 other Research Support, Non-U.S. Gov't; review-article; Review; Journal Article abstract-available 10.1242/dmm.050049 Understanding the neurological implications of acute and long COVID using brain organoids. García-González L, Martí-Sarrias A, Puertas MC, Bayón-Gil Á, Resa-Infante P, Martinez-Picado J, Navarro A, Acosta S. Dis Model Mech. 2023; 16 (7)
Rationale for combined therapies in severe-to-critical COVID-19 patients.
Gonzaga A, Andreu E, Hernández-Blasco LM, Meseguer R, [...], Soria B.
Front Immunol. 2023; 14
DOI: 10.3389/fimmu.2023.1232472
An unprecedented global social and economic impact as well as a significant number of fatalities have been brought on by the coronavirus disease 2019 (COVID-19), produced by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Acute SARS-CoV-2 infection can, in certain situations, cause immunological abnormalities, leading to an anomalous innate and adaptive immune response. While most patients only experience mild symptoms and recover without the need for mechanical ventilation, a substantial percentage of those who are affected develop severe respiratory illness, which can be fatal. The absence of effective therapies when disease progresses to a very severe condition coupled with the incomplete understanding of COVID-19's pathogenesis triggers the need to develop innovative therapeutic approaches for patients at high risk of mortality. As a result, we investigate the potential contribution of promising combinatorial cell therapy to prevent death in critical patients.
2023-09-11 2023 other review-article; Review; Journal Article abstract-available 10.3389/fimmu.2023.1232472 Rationale for combined therapies in severe-to-critical COVID-19 patients. Gonzaga A, Andreu E, Hernández-Blasco LM, Meseguer R, Al-Akioui-Sanz K, Soria-Juan B, Sanjuan-Gimenez JC, Ferreras C, Tejedo JR, Lopez-Lluch G, Goterris R, Maciá L, Sempere-Ortells JM, Hmadcha A, Borobia A, Vicario JL, Bonora A, Aguilar-Gallardo C, Poveda JL, Arbona C, Alenda C, Tarín F, Marco FM, Merino E, Jaime F, Ferreres J, Figueira JC, Cañada-Illana C, Querol S, Guerreiro M, Eguizabal C, Martín-Quirós A, Robles-Marhuenda Á, Pérez-Martínez A, Solano C, Soria B. Front Immunol. 2023; 14
Novel Spike-stabilized trimers with improved production protect K18-hACE2 mice and golden Syrian hamsters from the highly pathogenic SARS-CoV-2 Beta variant.
Ávila-Nieto C, Vergara-Alert J, Amengual-Rigo P, Ainsua-Enrich E, [...], Carrillo J.
Front Immunol. 2023; 14
DOI: 10.3389/fimmu.2023.1291972
Most COVID-19 vaccines are based on the SARS-CoV-2 Spike glycoprotein (S) or their subunits. However, S shows some structural instability that limits its immunogenicity and production, hampering the development of recombinant S-based vaccines. The introduction of the K986P and V987P (S-2P) mutations increases the production and immunogenicity of the recombinant S trimer, suggesting that these two parameters are related. Nevertheless, S-2P still shows some molecular instability and it is produced with low yield. Here we described a novel set of mutations identified by molecular modeling and located in the S2 region of the S-2P that increase its production up to five-fold. Besides their immunogenicity, the efficacy of two representative S-2P-based mutants, S-29 and S-21, protecting from a heterologous SARS-CoV-2 Beta variant challenge was assayed in K18-hACE2 mice (an animal model of severe SARS-CoV-2 disease) and golden Syrian hamsters (GSH) (a moderate disease model). S-21 induced higher level of WH1 and Delta variants neutralizing antibodies than S-2P in K18-hACE2 mice three days after challenge. Viral load in nasal turbinate and oropharyngeal samples were reduced in S-21 and S-29 vaccinated mice. Despite that, only the S-29 protein protected 100% of K18-hACE2 mice from severe disease. When GSH were analyzed, all immunized animals were protected from disease development irrespectively of the immunogen they received. Therefore, the higher yield of S-29, as well as its improved immunogenicity and efficacy protecting from the highly pathogenic SARS-CoV-2 Beta variant, pinpoint the S-29 mutant as an alternative to the S-2P protein for future SARS-CoV-2 vaccine development.
2023-12-04 2023 other Research Support, Non-U.S. Gov't; research-article; Journal Article abstract-available 10.3389/fimmu.2023.1291972 Novel Spike-stabilized trimers with improved production protect K18-hACE2 mice and golden Syrian hamsters from the highly pathogenic SARS-CoV-2 Beta variant. Ávila-Nieto C, Vergara-Alert J, Amengual-Rigo P, Ainsua-Enrich E, Brustolin M, Rodríguez de la Concepción ML, Pedreño-Lopez N, Rodon J, Urrea V, Pradenas E, Marfil S, Ballana E, Riveira-Muñoz E, Pérez M, Roca N, Tarrés-Freixas F, Carabelli J, Cantero G, Pons-Grífols A, Rovirosa C, Aguilar-Gurrieri C, Ortiz R, Barajas A, Trinité B, Lepore R, Muñoz-Basagoiti J, Perez-Zsolt D, Izquierdo-Useros N, Valencia A, Blanco J, Clotet B, Guallar V, Segalés J, Carrillo J. Front Immunol. 2023; 14
Animal models to study the neurological manifestations of the post-COVID-19 condition.
Usai C, Mateu L, Brander C, Vergara-Alert J, [...], Segalés J.
Lab Anim (NY). 2023; 52 (9)
DOI: 10.1038/s41684-023-01231-z
More than 40% of individuals infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have experienced persistent or relapsing multi-systemic symptoms months after the onset of coronavirus disease 2019 (COVID-19). This post-COVID-19 condition (PCC) has debilitating effects on the daily life of patients and encompasses a broad spectrum of neurological and neuropsychiatric symptoms including olfactory and gustative impairment, difficulty with concentration and short-term memory, sleep disorders and depression. Animal models have been instrumental to understand acute COVID-19 and validate prophylactic and therapeutic interventions. Similarly, studies post-viral clearance in hamsters, mice and nonhuman primates inoculated with SARS-CoV-2 have been useful to unveil some of the aspects of PCC. Transcriptomic alterations in the central nervous system, persistent activation of immune cells and impaired hippocampal neurogenesis seem to have a critical role in the neurological manifestations observed in animal models infected with SARS-CoV-2. Interestingly, the proinflammatory transcriptomic profile observed in the central nervous system of SARS-CoV-2-inoculated mice partially overlaps with the pathological changes that affect microglia in humans during Alzheimer's disease and aging, suggesting shared mechanisms between these conditions. None of the currently available animal models fully replicates PCC in humans; therefore, multiple models, together with the fine-tuning of experimental conditions, will probably be needed to understand the mechanisms of PCC neurological symptoms. Moreover, given that the intrinsic characteristics of the new variants of concern and the immunological status of individuals might influence PCC manifestations, more studies are needed to explore the role of these factors and their combinations in PCC, adding further complexity to the design of experimental models.
2023-08-24 2023 other Research Support, Non-U.S. Gov't; review-article; Review; Journal Article abstract-available 10.1038/s41684-023-01231-z Animal models to study the neurological manifestations of the post-COVID-19 condition. Usai C, Mateu L, Brander C, Vergara-Alert J, Segalés J. Lab Anim (NY). 2023; 52 (9)
Analysis of SARS-CoV-2 Emergent Variants Following AZD7442 (Tixagevimab/Cilgavimab) for Early Outpatient Treatment of COVID-19 (TACKLE Trial).
Kijak GH, Ahani B, Arbetter D, Chuecos F, [...], Streicher K.
Infect Dis Ther. 2023; 12 (12)
DOI: 10.1007/s40121-023-00882-2

Introduction

AZD7442 (tixagevimab/cilgavimab) comprises neutralising monoclonal antibodies (mAbs) that bind to distinct non-overlapping epitopes on the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. Viral evolution during mAb therapy can select for variants with reduced neutralisation susceptibility. We examined treatment-emergent SARS-CoV-2 variants during TACKLE (NCT04723394), a phase 3 study of AZD7442 for early outpatient treatment of coronavirus disease 2019 (COVID-19).

Methods

Non-hospitalised adults with mild-to-moderate COVID-19 were randomised and dosed ≤ 7 days from symptom onset with AZD7442 (n = 452) or placebo (n = 451). Next-generation sequencing of the spike gene was performed on SARS-CoV-2 reverse-transcription polymerase chain reaction-positive nasopharyngeal swabs at baseline and study days 3, 6, and 15 post dosing. SARS-CoV-2 lineages were assigned using spike nucleotide sequences. Amino acid substitutions were analysed at allele fractions (AF; % of sequence reads represented by substitution) ≥ 25% and 3% to 25%. In vitro susceptibility to tixagevimab, cilgavimab, and AZD7442 was evaluated for all identified treatment-emergent variants using a pseudotyped microneutralisation assay.

Results

Longitudinal spike sequences were available for 461 participants (AZD7442, n = 235; placebo, n = 226) and showed that treatment-emergent variants at any time were rare, with 5 (2.1%) AZD7442 participants presenting ≥ 1 substitution in tixagevimab/cilgavimab binding sites at AF ≥ 25%. At AF 3% to 25%, treatment-emergent variants were observed in 15 (6.4%) AZD7442 and 12 (5.3%) placebo participants. All treatment-emergent variants showed in vitro susceptibility to AZD7442.

Conclusion

These data indicate that AZD7442 creates a high genetic barrier for resistance and is a feasible option for COVID-19 treatment.
2023-11-02 2023 other research-article; Journal Article abstract-available 10.1007/s40121-023-00882-2 Analysis of SARS-CoV-2 Emergent Variants Following AZD7442 (Tixagevimab/Cilgavimab) for Early Outpatient Treatment of COVID-19 (TACKLE Trial). Kijak GH, Ahani B, Arbetter D, Chuecos F, Gopalakrishnan V, Beloor J, Brady T, Nguyen A, Roe TL, Schuko N, Zhang T, Hobbs FDR, Padilla F, Kelly EJ, Montgomery H, Streicher K. Infect Dis Ther. 2023; 12 (12)
Cell immunity to SARS-CoV-2 after natural infection and/or different vaccination regimens.
Culebras E, Martínez M, Novella C, León JM, [...], Ríos E.
Front Cell Infect Microbiol. 2024; 14
DOI: 10.3389/fcimb.2024.1370859

Background

The aim of the study was to evaluate the humoral and cellular immunity after SARS-CoV-2 infection and/or vaccination according to the type of vaccine, number of doses and combination of vaccines.

Methods

Volunteer subjects were sampled between September 2021 and July 2022 in Hospital Clínico San Carlos, Madrid (Spain). Participants had different immunological status against SARS-CoV-2: vaccinated and unvaccinated, with or without previous COVID-19 infection, including healthy and immunocompromised individuals. Determination of IgG against the spike protein S1 subunit receptor-binding domain (RBD) was performed by chemiluminescence microparticle immunoassay (CMIA) using the Architect i10000sr platform (Abbott). The SARS-CoV-2-specific T-cell responses were assessed by quantification of interferon gamma release using QuantiFERON SARS-CoV-2 assay (Qiagen).

Results

A total of 181 samples were collected, 170 were from vaccinated individuals and 11 from unvaccinated. Among the participants, 41 were aware of having previously been infected by SARS-CoV-2. Vaccinated people received one or two doses of the following vaccines against SARS-CoV-2: ChAdOx1-S (University of Oxford-AstraZeneca) (AZ) and/orBNT162b2 (Pfizer-BioNTech)(PZ). Subjects immunized with a third-booster dose received PZ or mRNA-1273 (Moderna-NIAID)(MD) vaccines. All vaccinees developed a positive humoral response (>7.1 BAU/ml), but the cellular response varied depending on the vaccination regimen. Only AZ/PZ combination and 3 doses of vaccination elicited a positive cellular response (median concentration of IFN- γ > 0.3 IU/ml). Regarding a two-dose vaccination regimen, AZ/PZ combination induced the highest humoral and cellular immunity. A booster with mRNA vaccine resulted in increases in median levels of IgG-Spike antibodies and IFN-γ as compared to those of two-dose of any vaccine. Humoral and cellular immunity levels were significantly higher in participants with previous infection compared to those without infection.

Conclusion

Heterologous vaccination (AZ/PZ) elicited the strongest immunity among the two-dose vaccination regimens. The immunity offered by the third-booster dose of SARS-CoV-2 vaccine depends not only on the type of vaccine administered but also on previous doses and prior infection. Previous exposure to SARS-CoV-2 antigens by infection strongly affect immunity of vaccinated individuals.
2024-03-20 2024 other research-article; Journal Article abstract-available 10.3389/fcimb.2024.1370859 Cell immunity to SARS-CoV-2 after natural infection and/or different vaccination regimens. Culebras E, Martínez M, Novella C, León JM, Marcos E, Delgado-Iribarren A, Ríos E. Front Cell Infect Microbiol. 2024; 14
Impact on the first year of life of newborns with gestational infection by SARS-COV-2. Analysis of auditory effects.
Sanz López L, Lora Díaz J, Castañeda-Vozmediano R, Mata-Castro N.
Heliyon. 2024; 10 (1)
DOI: 10.1016/j.heliyon.2023.e23482

Introduction

One of the causes of congenital hearing loss are infections suffered by the mother during pregnancy. The objective of this study was to investigate the effects on hearing in newborns to SARS-CoV-2 seropositive mothers during pregnancy. We also studied the hearing impact in the first year of life of the newborns to investigate whether neonatal infection produced a risk of infantile sensorineural hearing loss.

Material and methods

All children born in our center whose mother had been infected with SARS-CoV-2 positive COVID were included and were audiologically studied at two and a half months and at one year of life. All infants were evaluated by brainstem evoked response audiometry (BERA) and auditory steady-state responses (ASSR).

Results

The range of the latencies for BERA founded were inside the desired ranges of normality both at two and a half months and at one year of life No significant differences by sex and ears were found in the BERA performed (p > 0,05). The mean ASSR values were found to be significantly below 30 dB in all frequencies studied both at two and a half months, and at one year of life (p < 0,05).

Conclusion

There is no association between COVID-19 infection during pregnancy and neonatal hearing loss. Further studies are needed to clarify this field since it is still unclear whether pregnant women infected with SARS-CoV-2 can produce hearing alterations in their newborns according to the current evidence in the literature.
2023-12-13 2023 other research-article; Journal Article abstract-available 10.1016/j.heliyon.2023.e23482 Impact on the first year of life of newborns with gestational infection by SARS-COV-2. Analysis of auditory effects. Sanz López L, Lora Díaz J, Castañeda-Vozmediano R, Mata-Castro N. Heliyon. 2024; 10 (1)
Prognostic Value of D-dimer to Lymphocyte Ratio (DLR) in Hospitalized Coronavirus Disease 2019 (COVID-19) Patients: A Validation Study in a National Cohort.
Oblitas CM, Demelo-Rodríguez P, Alvarez-Sala-Walther LA, Rubio-Rivas M, [...], SEMI-COVID-19 Network.
Viruses. 2024; 16 (3)
DOI: 10.3390/v16030335

Background

This study aimed to validate the role of the D-dimer to lymphocyte ratio (DLR) for mortality prediction in a large national cohort of hospitalized coronavirus disease 2019 (COVID-19) patients.

Methods

A retrospective, multicenter, observational study that included hospitalized patients due to SARS-CoV-2 infection in Spain was conducted from March 2020 to March 2022. All biomarkers and laboratory indices analyzed were measured once at admission.

Results

A total of 10,575 COVID-19 patients were included in this study. The mean age of participants was 66.9 (±16) years, and 58.6% (6202 patients) of them were male. The overall mortality rate was 16.3% (n = 1726 patients). Intensive care unit admission was needed in 10.5% (n = 1106 patients), non-invasive mechanical ventilation was required in 8.8% (n = 923 patients), and orotracheal intubation was required in 7.5% (789 patients). DLR presented a c-statistic of 0.69 (95% CI, 0.68-0.71) for in-hospital mortality with an optimal cut-off above 1. Multivariate analysis showed an independent association for in-hospital mortality for DLR > 1 (adjusted OR 2.09, 95% CI 1.09-4.04; p = 0.03); in the same way, survival analysis showed a higher mortality risk for DLR > 1 (HR 2.24; 95% CI 2.03-2.47; p < 0.01). Further, no other laboratory indices showed an independent association for mortality in multivariate analysis.

Conclusions

This study confirmed the usefulness of DLR as a prognostic biomarker for mortality associated with SARS-CoV-2 infection, being an accessible, cost-effective, and easy-to-use biomarker in daily clinical practice.
2024-02-22 2024 other research-article; Multicenter Study; Journal Article; Observational Study abstract-available 10.3390/v16030335 Prognostic Value of D-dimer to Lymphocyte Ratio (DLR) in Hospitalized Coronavirus Disease 2019 (COVID-19) Patients: A Validation Study in a National Cohort. Oblitas CM, Demelo-Rodríguez P, Alvarez-Sala-Walther LA, Rubio-Rivas M, Navarro-Romero F, Giner Galvañ V, de Jorge-Huerta L, Fonseca Aizpuru E, García García GM, Beato Pérez JL, Pesqueira Fontan PM, Artero Mora A, Vargas Núñez JA, Ramírez Perea N, García Bruñén JM, Roy Vallejo E, Perales-Fraile I, Gil Sánchez R, López Castro J, Martínez González ÁL, Díez García LF, Aroza Espinar M, Casas-Rojo JM, Millán Núñez-Cortés J, SEMI-COVID-19 Network. Viruses. 2024; 16 (3)
Type 2 and Non-type 2 Inflammation in the Upper Airways: Cellular and Molecular Alterations in Olfactory Neuroepithelium Cell Populations.
Marin C, Alobid I, López-Chacón M, VanStrahlen CR, [...], Mullol J.
Curr Allergy Asthma Rep. 2024; 24 (4)
DOI: 10.1007/s11882-024-01137-x

Purpose of review

Neurogenesis occurring in the olfactory epithelium is critical to continuously replace olfactory neurons to maintain olfactory function, but is impaired during chronic type 2 and non-type 2 inflammation of the upper airways. In this review, we describe the neurobiology of olfaction and the olfactory alterations in chronic rhinosinusitis with nasal polyps (type 2 inflammation) and post-viral acute rhinosinusitis (non-type 2 inflammation), highlighting the role of immune response attenuating olfactory neurogenesis as a possibly mechanism for the loss of smell in these diseases.

Recent findings

Several studies have provided relevant insights into the role of basal stem cells as direct participants in the progression of chronic inflammation identifying a functional switch away from a neuro-regenerative phenotype to one contributing to immune defense, a process that induces a deficient replacement of olfactory neurons. The interaction between olfactory stem cells and immune system might critically underlie ongoing loss of smell in type 2 and non-type 2 inflammatory upper airway diseases. In this review, we describe the neurobiology of olfaction and the olfactory alterations in type 2 and non-type 2 inflammatory upper airway diseases, highlighting the role of immune response attenuating olfactory neurogenesis, as a possibly mechanism for the lack of loss of smell recovery.
2024-03-16 2024 other review-article; Review; Journal Article abstract-available 10.1007/s11882-024-01137-x Type 2 and Non-type 2 Inflammation in the Upper Airways: Cellular and Molecular Alterations in Olfactory Neuroepithelium Cell Populations. Marin C, Alobid I, López-Chacón M, VanStrahlen CR, Mullol J. Curr Allergy Asthma Rep. 2024; 24 (4)
Personalized Assessment of Mortality Risk and Hospital Stay Duration in Hospitalized Patients with COVID-19 Treated with Remdesivir: A Machine Learning Approach.
Ramón A, Bas A, Herrero S, Blasco P, [...], Mateo J.
J Clin Med. 2024; 13 (7)
DOI: 10.3390/jcm13071837
Background: Despite advancements in vaccination, early treatments, and understanding of SARS-CoV-2, its impact remains significant worldwide. Many patients require intensive care due to severe COVID-19. Remdesivir, a key treatment option among viral RNA polymerase inhibitors, lacks comprehensive studies on factors associated with its effectiveness. Methods: We conducted a retrospective study in 2022, analyzing data from 252 hospitalized COVID-19 patients treated with remdesivir. Six machine learning algorithms were compared to predict factors influencing remdesivir's clinical benefits regarding mortality and hospital stay. Results: The extreme gradient boost (XGB) method showed the highest accuracy for both mortality (95.45%) and hospital stay (94.24%). Factors associated with worse outcomes in terms of mortality included limitations in life support, ventilatory support needs, lymphopenia, low albumin and hemoglobin levels, flu and/or coinfection, and cough. For hospital stay, factors included vaccine doses, lung density, pulmonary radiological status, comorbidities, oxygen therapy, troponin, lactate dehydrogenase levels, and asthenia. Conclusions: These findings underscore XGB's effectiveness in accurately categorizing COVID-19 patients undergoing remdesivir treatment.
2024-03-22 2024 other research-article; Journal Article abstract-available 10.3390/jcm13071837 Personalized Assessment of Mortality Risk and Hospital Stay Duration in Hospitalized Patients with COVID-19 Treated with Remdesivir: A Machine Learning Approach. Ramón A, Bas A, Herrero S, Blasco P, Suárez M, Mateo J. J Clin Med. 2024; 13 (7)
SARS-CoV-2 infection induces robust mucosal antibody responses in the upper respiratory tract.
Escalera A, Rojo-Fernandez A, Rombauts A, Abelenda-Alonso G, [...], Aydillo T.
iScience. 2024; 27 (3)
DOI: 10.1016/j.isci.2024.109210
Despite multiple research efforts to characterize coronavirus disease 2019 (COVID-19) in humans, there is no clear data on the specific role of mucosal immunity on COVID-19 disease. Here, we longitudinally profile the antibody response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and seasonal HCoV-OC43 S proteins in serum and nasopharyngeal swabs from COVID-19 patients. Results showed that specific antibody responses against SARS-CoV-2 and HCoV-OC43 S proteins can be detected in the upper respiratory tract. We found that COVID-19 patients mounted a robust mucosal antibody response against SARS-CoV-2 S with specific secretory immunoglobulin A (sIgA), IgA, IgG, and IgM antibody subtypes detected in the nasal swabs. Additionally, COVID-19 patients showed IgG, IgA, and sIgA responses against HCoV-OC43 S in the local mucosa, whereas no specific IgM was detected. Interestingly, mucosal antibody titers against SARS-CoV-2 peaked at day 7, whereas HCoV-OC43 titers peaked earlier at day 3 post-recruitment, suggesting an immune memory recall to conserved epitopes of beta-HCoVs in the upper respiratory tract.
2024-02-10 2024 other research-article; Journal Article abstract-available 10.1016/j.isci.2024.109210 SARS-CoV-2 infection induces robust mucosal antibody responses in the upper respiratory tract. Escalera A, Rojo-Fernandez A, Rombauts A, Abelenda-Alonso G, Carratalà J, García-Sastre A, Aydillo T. iScience. 2024; 27 (3)
A Comparison between SARS-CoV-2 and Gram-Negative Bacteria-Induced Hyperinflammation and Sepsis
Brandenburg K, Ferrer-Espada R, De Tejada GM, Nehls C, [...], Garidel P.
Preprints.org; 2023.
DOI: 10.20944/preprints202308.2077.v1
Sepsis is a life-threatening condition caused by the body's overwhelming response to an infection, such as pneumonia or urinary tract infection. It occurs when the immune system releases cytokines into the bloodstream, triggering widespread inflammation. If not treated, it can lead to organ failure and death. Unfortunately, sepsis has a high mortality rate, with studies reporting rates ranging from 20% to over 50%, depending on the severity and promptness of treatment. According to the World Health Organization (WHO), the annual death toll in the world is about 11 million. One of the main toxins responsible for inflammation induction are lipopolysaccharides (LPS, endotoxin) from Gram-negative bacteria, which ranks among the most potent immunostimulants found in nature. Antibiotics are consistently prescribed as a part of anti-sepsis-therapy. However, antibiotic therapy (i) is increasingly ineffective due to resistance development and (ii) most antibiotics are unable to bind and neutralize LPS, a prerequisite to inhibit the interaction of endotoxin with its cellular receptor complex, namely Toll-like receptor 4 (TLR4)/MD-2, responsible for the intracellular cascade leading to pro-inflammatory cytokine secretion. The pandemic virus SARS-CoV-2 has infected hundreds of millions of humans worldwide since its emergence in 2019. The COVID-19 (Coronavirus disease-19) caused by this virus is associated with high lethality, particularly for elderly and immunocompromised people. As of August 2023, nearly 7 million deaths were reported worldwide due to this disease. According to some reported studies, upregulation of TLR4 and the subsequent inflammatory signaling detected in COVID-19 patients “mimics bacterial sepsis”. Furthermore, the immune response to SARS-CoV-2 was described by others as “mirror image of sepsis”. Similarly, the cytokine profile in sera from severe COVID-19 patients was very similar to those suffering from the acute respiratory distress syndrome (ARDS) and sepsis. Finally, the severe COVID-19 infection was frequently accompanied by bacterial co-infections, as well as by the presence of significant LPS concentrations. These data indicate similarity and interdependences of both syndromes, but also significant differences which will be discussed in the present review.
2023-08-31 2023 other Preprint abstract-available 10.20944/preprints202308.2077.v1 A Comparison between SARS-CoV-2 and Gram-Negative Bacteria-Induced Hyperinflammation and Sepsis Brandenburg K, Ferrer-Espada R, De Tejada GM, Nehls C, Fukuoka S, Mauss K, Weindl G, Garidel P. Preprints.org; 2023.
COVID-19 and cardiovascular disease in patients with chronic kidney disease.
Del Vecchio L, Balafa O, Dounousi E, Ekart R, [...], Mallamaci F.
Nephrol Dial Transplant. 2024; 39 (2)
DOI: 10.1093/ndt/gfad170
Millions of people worldwide have chronic kidney disease (CKD). Affected patients are at high risk for cardiovascular (CV) disease for several reasons. Among various comorbidities, CKD is associated with the more severe forms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. This is particularly true for patients receiving dialysis or for kidney recipients. From the start of the SARS-CoV-2 pandemic, several CV complications have been observed in affected subjects, spanning acute inflammatory manifestations, CV events, thrombotic episodes and arrythmias. Several pathogenetic mechanisms have been hypothesized, including direct cytopathic viral effects on the myocardium, endothelial damage and hypercoagulability. This spectrum of disease can occur during the acute phase of the infection, but also months after recovery. This review is focussed on the CV complications of coronavirus disease 2019 (COVID-19) with particular interest in their implications for the CKD population.
2024-01-01 2024 other review-article; Review; Journal Article abstract-available 10.1093/ndt/gfad170 COVID-19 and cardiovascular disease in patients with chronic kidney disease. Del Vecchio L, Balafa O, Dounousi E, Ekart R, Fernandez BF, Mark PB, Sarafidis P, Valdivielso JM, Ferro CJ, Mallamaci F. Nephrol Dial Transplant. 2024; 39 (2)
Discovery of a novel inhibitor of macropinocytosis with antiviral activity
Porebski B, Christ W, Corman A, Haraldsson M, [...], Fernandez-Capetillo O.
bioRxiv; 2023.
DOI: 10.1101/2023.10.25.563967

SUMMARY

Several viruses hijack various forms of endocytosis in order to infect host cells. Here, we report the discovery of a new molecule with antiviral properties that we named virapinib, which limits viral entry by macropinocytosis. The identification of virapinib derives from a chemical screen using High-Throughput Microscopy, where we identified new chemical entities capable of preventing infection with a pseudotype virus expressing the spike (S) protein from SARS-CoV-2. Subsequent experiments confirmed the capacity of virapinib to inhibit infection by SARS-CoV-2, as well as by additional viruses, such as Monkeypox virus and TBEV. Mechanistic analyses revealed that the compound inhibited macropinocytosis, limiting this entry route for the viruses. Importantly, virapinib has no significant toxicity to host cells. In summary, we present a new molecule that inhibits viral entry via the endocytic route, offering a new alternative to prevent viral infection.
2023-10-26 2023 other Preprint abstract-available 10.1101/2023.10.25.563967 Discovery of a novel inhibitor of macropinocytosis with antiviral activity Porebski B, Christ W, Corman A, Haraldsson M, Barz M, Lidemalm L, Häggblad M, Ilmain J, Wright SC, Murga M, Shlegel J, Sezgin E, Bhabha G, Lauschke VM, Lafarga M, Klingström J, Huhn D, Fernandez-Capetillo O. bioRxiv; 2023.
Predictive Model for Mortality in Severe COVID-19 Patients across the Six Pandemic Waves.
Casillas N, Ramón A, Torres AM, Blasco P, [...], Mateo J.
Viruses. 2023; 15 (11)
DOI: 10.3390/v15112184
The impact of SARS-CoV-2 infection remains substantial on a global scale, despite widespread vaccination efforts, early therapeutic interventions, and an enhanced understanding of the disease's underlying mechanisms. At the same time, a significant number of patients continue to develop severe COVID-19, necessitating admission to intensive care units (ICUs). This study aimed to provide evidence concerning the most influential predictors of mortality among critically ill patients with severe COVID-19, employing machine learning (ML) techniques. To accomplish this, we conducted a retrospective multicenter investigation involving 684 patients with severe COVID-19, spanning from 1 June 2020 to 31 March 2023, wherein we scrutinized sociodemographic, clinical, and analytical data. These data were extracted from electronic health records. Out of the six supervised ML methods scrutinized, the extreme gradient boosting (XGB) method exhibited the highest balanced accuracy at 96.61%. The variables that exerted the greatest influence on mortality prediction encompassed ferritin, fibrinogen, D-dimer, platelet count, C-reactive protein (CRP), prothrombin time (PT), invasive mechanical ventilation (IMV), PaFi (PaO2/FiO2), lactate dehydrogenase (LDH), lymphocyte levels, activated partial thromboplastin time (aPTT), body mass index (BMI), creatinine, and age. These findings underscore XGB as a robust candidate for accurately classifying patients with COVID-19.
2023-10-30 2023 other research-article; Multicenter Study; Journal Article abstract-available 10.3390/v15112184 Predictive Model for Mortality in Severe COVID-19 Patients across the Six Pandemic Waves. Casillas N, Ramón A, Torres AM, Blasco P, Mateo J. Viruses. 2023; 15 (11)
SARS-CoV-2 ORF8 accessory protein is a virulence factor.
Bello-Perez M, Hurtado-Tamayo J, Mykytyn AZ, Lamers MM, [...], Sola I.
mBio. 2023; 14 (5)
DOI: 10.1128/mbio.00451-23

Importance

The relevance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ORF8 in the pathogenesis of COVID-19 is unclear. Virus natural isolates with deletions in ORF8 were associated with wild milder disease, suggesting that ORF8 might contribute to SARS-CoV-2 virulence. This manuscript shows that ORF8 is involved in inflammation and in the activation of macrophages in two experimental systems: humanized K18-hACE2 transgenic mice and organoid-derived human airway cells. These results identify ORF8 protein as a potential target for COVID-19 therapies.
2023-08-25 2023 other research-article; Journal Article abstract-available 10.1128/mbio.00451-23 SARS-CoV-2 ORF8 accessory protein is a virulence factor. Bello-Perez M, Hurtado-Tamayo J, Mykytyn AZ, Lamers MM, Requena-Platek R, Schipper D, Muñoz-Santos D, Ripoll-Gómez J, Esteban A, Sánchez-Cordón PJ, Enjuanes L, Haagmans BL, Sola I. mBio. 2023; 14 (5)
Special Issue "Molecular and Genetic Aspects of SARS-CoV-2 Infection and COVID-19 Disease".
Cardona F, Pérez-Tur J.
Int J Mol Sci. 2024; 25 (9)
DOI: 10.3390/ijms25094670
We are pleased to present the first and second editions of this Special Issue, titled "Molecular and Genetic Aspects of SARS-CoV-2 Infection and COVID-19 Disease", of the International Journal of Molecular Sciences [...].
2024-04-25 2024 other Introductory Journal Article; Editorial abstract-available 10.3390/ijms25094670 Special Issue "Molecular and Genetic Aspects of SARS-CoV-2 Infection and COVID-19 Disease". Cardona F, Pérez-Tur J. Int J Mol Sci. 2024; 25 (9)
Plasma of COVID-19 Patients Does Not Alter Electrical Resistance of Human Endothelial Blood-Brain Barrier In Vitro.
Pociūtė A, Kriaučiūnaitė K, Kaušylė A, Zablockienė B, [...], Pivoriūnas A.
Function (Oxf). 2024; 5 (2)
DOI: 10.1093/function/zqae002
The pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 instigated the most serious global health crisis. Clinical presentation of COVID-19 frequently includes severe neurological and neuropsychiatric symptoms. However, it is presently unknown whether and to which extent pathological impairment of blood-brain barrier (BBB) contributes to the development of neuropathology during COVID-19 progression. In the present study, we used human induced pluripotent stem cells-derived brain endothelial cells (iBECs) to study the effects of blood plasma derived from COVID-19 patients on the BBB integrity in vitro. We also performed a comprehensive analysis of the cytokine and chemokine profiles in the plasma of COVID-19 patients, healthy and recovered individuals. We found significantly increased levels of interferon γ-induced protein 10 kDa, hepatocyte growth factor, and interleukin-18 in the plasma of COVID-19 patients. However, blood plasma from COVID-19 patients did not affect transendothelial electrical resistance in iBEC monolayers. Our results demonstrate that COVID-19-associated blood plasma inflammatory factors do not affect BBB paracellular pathway directly and suggest that pathological remodeling (if any) of BBB during COVID-19 may occur through indirect or yet unknown mechanisms.
2024-01-09 2024 other research-article; Journal Article abstract-available 10.1093/function/zqae002 Plasma of COVID-19 Patients Does Not Alter Electrical Resistance of Human Endothelial Blood-Brain Barrier In Vitro. Pociūtė A, Kriaučiūnaitė K, Kaušylė A, Zablockienė B, Alčauskas T, Jelinskaitė A, Rudėnaitė A, Jančorienė L, Ročka S, Verkhratsky A, Pivoriūnas A. Function (Oxf). 2024; 5 (2)
Single-Molecule Investigation of the Binding Interface Stability of SARS-CoV-2 Variants with ACE2.
Ray A, Minh Tran TT, Santos Natividade RD, Moreira RA, [...], Alsteens D.
ACS Nanosci Au. 2024; 4 (2)
DOI: 10.1021/acsnanoscienceau.3c00060
The SARS-CoV-2 pandemic spurred numerous research endeavors to comprehend the virus and mitigate its global severity. Understanding the binding interface between the virus and human receptors is pivotal to these efforts and paramount to curbing infection and transmission. Here we employ atomic force microscopy and steered molecular dynamics simulation to explore SARS-CoV-2 receptor binding domain (RBD) variants and angiotensin-converting enzyme 2 (ACE2), examining the impact of mutations at key residues upon binding affinity. Our results show that the Omicron and Delta variants possess strengthened binding affinity in comparison to the Mu variant. Further, using sera from individuals either vaccinated or with acquired immunity following Delta strain infection, we assess the impact of immunity upon variant RBD/ACE2 complex formation. Single-molecule force spectroscopy analysis suggests that vaccination before infection may provide stronger protection across variants. These results underscore the need to monitor antigenic changes in order to continue developing innovative and effective SARS-CoV-2 abrogation strategies.
2024-03-08 2024 other rapid-communication; Journal Article abstract-available 10.1021/acsnanoscienceau.3c00060 Single-Molecule Investigation of the Binding Interface Stability of SARS-CoV-2 Variants with ACE2. Ray A, Minh Tran TT, Santos Natividade RD, Moreira RA, Simpson JD, Mohammed D, Koehler M, L Petitjean SJ, Zhang Q, Bureau F, Gillet L, Poma AB, Alsteens D. ACS Nanosci Au. 2024; 4 (2)
Preclinical immune efficacy against SARS-CoV-2 beta B.1.351 variant by MVA-based vaccine candidates.
Pérez P, Albericio G, Astorgano D, Flores S, [...], García-Arriaza J.
Front Immunol. 2023; 14
DOI: 10.3389/fimmu.2023.1264323
The constant appearance of new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VoCs) has jeopardized the protective capacity of approved vaccines against coronavirus disease-19 (COVID-19). For this reason, the generation of new vaccine candidates adapted to the emerging VoCs is of special importance. Here, we developed an optimized COVID-19 vaccine candidate using the modified vaccinia virus Ankara (MVA) vector to express a full-length prefusion-stabilized SARS-CoV-2 spike (S) protein, containing 3 proline (3P) substitutions in the S protein derived from the beta (B.1.351) variant, termed MVA-S(3Pbeta). Preclinical evaluation of MVA-S(3Pbeta) in head-to-head comparison to the previously generated MVA-S(3P) vaccine candidate, expressing a full-length prefusion-stabilized Wuhan S protein (with also 3P substitutions), demonstrated that two intramuscular doses of both vaccine candidates fully protected transgenic K18-hACE2 mice from a lethal challenge with SARS-CoV-2 beta variant, reducing mRNA and infectious viral loads in the lungs and in bronchoalveolar lavages, decreasing lung histopathological lesions and levels of proinflammatory cytokines in the lungs. Vaccination also elicited high titers of anti-S Th1-biased IgGs and neutralizing antibodies against ancestral SARS-CoV-2 Wuhan strain and VoCs alpha, beta, gamma, delta, and omicron. In addition, similar systemic and local SARS-CoV-2 S-specific CD4+ and CD8+ T-cell immune responses were elicited by both vaccine candidates after a single intranasal immunization in C57BL/6 mice. These preclinical data support clinical evaluation of MVA-S(3Pbeta) and MVA-S(3P), to explore whether they can diversify and potentially increase recognition and protection of SARS-CoV-2 VoCs.
2023-12-12 2023 other Research Support, Non-U.S. Gov't; research-article; Journal Article abstract-available 10.3389/fimmu.2023.1264323 Preclinical immune efficacy against SARS-CoV-2 beta B.1.351 variant by MVA-based vaccine candidates. Pérez P, Albericio G, Astorgano D, Flores S, Sánchez-Corzo C, Sánchez-Cordón PJ, Luczkowiak J, Delgado R, Casasnovas JM, Esteban M, García-Arriaza J. Front Immunol. 2023; 14
Vaccinia Virus Strain Mva Expressing a Prefusion-Stabilized SARS-CoV-2 Spike Glycoprotein Induces Robust Protection and Prevents Brain Infection in Mouse and Hamster Models
Lorenzo MM, Marín-López A, Chiem K, Jimenez-Cabello L, [...], Blasco R.
Preprints.org; 2023.
DOI: 10.20944/preprints202305.0218.v1
The COVID-19 pandemic has underscored the importance of swift responses and the necessity of dependable technologies for vaccine development. Our team previously developed a fast cloning system for the modified vaccinia virus Ankara (MVA) vaccine platform. In this study, we report the construction and preclinical testing of a recombinant MVA vaccine obtained using this system. We obtained recombinant MVA expressing the unmodified full-length SARS-CoV-2 spike (S) protein containing the D614G amino acid substitution (MVA-Sdg) and a version expressing a modified S protein containing amino acid substitutions designed to stabilize the protein a in a pre-fusion conformation (MVA-Spf). S protein expressed by MVA-Sdg was found to be expressed and correctly processed and transported to the cell surface, where it efficiently produced cell-cell fusion. Version Spf, however, was not proteolytically processed and despite being transported to the plasma membrane, it failed to induce cell-cell fusion. We assessed both vaccine candidates in prime-boost regimens in the susceptible transgenic K18-human angiotensin converting enzyme 2 (K18-hACE2) mice and in golden Syrian hamsters. Robust immunity and protection from disease was induced with either vaccine in both animal models. Remarkably, the MVA-Spf vaccine candidate produced higher levels of antibodies, a stronger T cell response, and a higher degree of protection from challenge. In addition, the levels of SARS-CoV-2 in the brain of MVA-Spf inoculated mice was decreased to undetectable levels. Those results add to our current experience and range of vaccine vectors and technologies for developing a safe and effective COVID-19 vaccine
2023-05-04 2023 other Preprint abstract-available 10.20944/preprints202305.0218.v1 Vaccinia Virus Strain Mva Expressing a Prefusion-Stabilized SARS-CoV-2 Spike Glycoprotein Induces Robust Protection and Prevents Brain Infection in Mouse and Hamster Models Lorenzo MM, Marín-López A, Chiem K, Jimenez-Cabello L, Ullah I, Utrilla-Trigo S, Calvo-Pinilla E, Lorenzo G, Moreno S, Ye C, Park J, Matía A, Brun A, Sánchez-Puig JM, Nogales A, Mothes W, Uchil PD, Kumar P, Ortego J, Fikrig E, Martinez-Sobrido L, Blasco R. Preprints.org; 2023.
Myocardial Injury in COVID-19 and Its Implications in Short- and Long-Term Outcomes.
Izquierdo-Marquisá A, Cubero-Gallego H, Aparisi Á, Vaquerizo B, [...], Ribas-Barquet N.
Front Cardiovasc Med. 2022; 9
DOI: 10.3389/fcvm.2022.901245
COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still a pandemic with high mortality and morbidity rates. Clinical manifestation is widely variable, including asymptomatic or mild respiratory tract illness to severe pneumonia and death. Myocardial injury is a significant pathogenic feature of COVID-19 and it is associated with worse in-hospital outcomes, mainly due to a higher number of hospital readmissions, with over 50% mortality. These findings suggest that myocardial injury would identify COVID-19 patients with higher risk during active infection and mid-term follow-up. Potential contributors responsible for myocardial damage are myocarditis, vasculitis, acute inflammation, type 1 and type 2 myocardial infarction. However, there are few data about cardiac sequelae and its long-term consequences. Thus, the optimal screening tool for residual cardiac sequelae, clinical follow-up, and the benefits of a specific cardiovascular therapy during the convalescent phase remains unknown. This mini-review explores the different mechanisms of myocardial injury related to COVID-19 and its short and long-term implications.
2022-05-26 2022 other review-article; Review; Journal Article abstract-available 10.3389/fcvm.2022.901245 Myocardial Injury in COVID-19 and Its Implications in Short- and Long-Term Outcomes. Izquierdo-Marquisá A, Cubero-Gallego H, Aparisi Á, Vaquerizo B, Ribas-Barquet N. Front Cardiovasc Med. 2022; 9
The Microbiota in Long COVID.
Álvarez-Santacruz C, Tyrkalska SD, Candel S.
Int J Mol Sci. 2024; 25 (2)
DOI: 10.3390/ijms25021330
Interest in the coronavirus disease 2019 (COVID-19) has progressively decreased lately, mainly due to the great effectivity of vaccines. Furthermore, no new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants able to circumvent the protection of these vaccines, while presenting high transmissibility and/or lethality, have appeared. However, long COVID has emerged as a huge threat to human health and economy globally. The human microbiota plays an important role in health and disease, participating in the modulation of innate and adaptive immune responses. Thus, multiple studies have found that the nasopharyngeal microbiota is altered in COVID-19 patients, with these changes associated with the onset and/or severity of the disease. Nevertheless, although dysbiosis has also been reported in long COVID patients, mainly in the gut, little is known about the possible involvement of the microbiota in the development of this disease. Therefore, in this work, we aim to fill this gap in the knowledge by discussing and comparing the most relevant studies that have been published in this field up to this point. Hence, we discuss that the relevance of long COVID has probably been underestimated, and that the available data suggest that the microbiota could be playing a pivotal role on the pathogenesis of the disease. Further research to elucidate the involvement of the microbiota in long COVID will be essential to explore new therapeutic strategies based on manipulation of the microbiota.
2024-01-22 2024 other review-article; Review; Journal Article abstract-available 10.3390/ijms25021330 The Microbiota in Long COVID. Álvarez-Santacruz C, Tyrkalska SD, Candel S. Int J Mol Sci. 2024; 25 (2)
Identification of FasL as a crucial host factor driving COVID-19 pathology and lethality.
Albert MC, Uranga-Murillo I, Arias M, De Miguel D, [...], Walczak H.
Cell Death Differ. 2024; 31 (5)
DOI: 10.1038/s41418-024-01278-6
The dysregulated immune response and inflammation resulting in severe COVID-19 are still incompletely understood. Having recently determined that aberrant death-ligand-induced cell death can cause lethal inflammation, we hypothesized that this process might also cause or contribute to inflammatory disease and lung failure following SARS-CoV-2 infection. To test this hypothesis, we developed a novel mouse-adapted SARS-CoV-2 model (MA20) that recapitulates key pathological features of COVID-19. Concomitantly with occurrence of cell death and inflammation, FasL expression was significantly increased on inflammatory monocytic macrophages and NK cells in the lungs of MA20-infected mice. Importantly, therapeutic FasL inhibition markedly increased survival of both, young and old MA20-infected mice coincident with substantially reduced cell death and inflammation in their lungs. Intriguingly, FasL was also increased in the bronchoalveolar lavage fluid of critically-ill COVID-19 patients. Together, these results identify FasL as a crucial host factor driving the immuno-pathology that underlies COVID-19 severity and lethality, and imply that patients with severe COVID-19 may significantly benefit from therapeutic inhibition of FasL.
2024-03-21 2024 other research-article; Journal Article abstract-available 10.1038/s41418-024-01278-6 Identification of FasL as a crucial host factor driving COVID-19 pathology and lethality. Albert MC, Uranga-Murillo I, Arias M, De Miguel D, Peña N, Montinaro A, Varanda AB, Theobald SJ, Areso I, Saggau J, Koch M, Liccardi G, Peltzer N, Rybniker J, Hurtado-Guerrero R, Merino P, Monzón M, Badiola JJ, Reindl-Schwaighofer R, Sanz-Pamplona R, Cebollada-Solanas A, Megyesfalvi Z, Dome B, Secrier M, Hartmann B, Bergmann M, Pardo J, Walczak H. Cell Death Differ. 2024; 31 (5)
Increased expression of SCARF genes favoring SARS-CoV-2 infection in key target organs in CKD.
Carriazo S, Ribagorda M, Pintor-Chocano A, Perez-Gomez MV, [...], Sanchez-Niño MD.
Clin Kidney J. 2023; 16 (12)
DOI: 10.1093/ckj/sfad220

Background

Chronic kidney disease (CKD), especially diabetic CKD, is the condition that most increases the risk of lethal coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the underlying molecular mechanisms are unclear. SARS-CoV-2 and coronavirus-associated receptors and factors (SCARFs) regulate coronavirus cell entry and/or replication. We hypothesized that CKD may alter the expression of SCARF genes.

Methods

A literature search identified 34 SCARF genes of which we selected 21 involved in interactions between SARS-CoV/SARS-CoV-2 and host cells, and assessed their mRNA expression in target tissues of COVID-19 (kidneys, lungs, aorta and heart) in mice with adenine-induced CKD.

Results

Twenty genes were differentially expressed in at least one organ in mice with CKD. For 15 genes, the differential expression would be expected to favor SARS-CoV-2 infection and/or severity. Of these 15 genes, 13 were differentially expressed in the kidney and 8 were validated in human CKD kidney transcriptomics datasets, including those for the most common cause of CKD, diabetic nephropathy. Two genes reported to protect from SARS-CoV-2 were downregulated in at least two non-kidney target organs: Ifitm3 encoding interferon-induced transmembrane protein 3 (IFITM3) in lung and Ly6e encoding lymphocyte antigen 6 family member 6 (LY6E) in aorta.

Conclusion

CKD, including diabetic CKD, is associated with the differential expression of multiple SCARF genes in target organs of COVID-19, some of which may sensitize to SARS-CoV-2 infection. This information may facilitate developing therapeutic strategies aimed at decreasing COVID-19 severity in patients with CKD.
2023-09-05 2023 other research-article; Journal Article abstract-available 10.1093/ckj/sfad220 Increased expression of SCARF genes favoring SARS-CoV-2 infection in key target organs in CKD. Carriazo S, Ribagorda M, Pintor-Chocano A, Perez-Gomez MV, Ortiz A, Sanchez-Niño MD. Clin Kidney J. 2023; 16 (12)
Bidirectional interplay between SARS-CoV-2 and autophagy.
Zhou H, Hu Z, Castro-Gonzalez S.
mBio. 2023; 14 (4)
DOI: 10.1128/mbio.01020-23
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as the causative agent of the recent COVID-19 pandemic, continues representing one of the main health concerns worldwide. Autophagy, in addition to its role in cellular homeostasis and metabolism, plays an important part for the host antiviral immunity. However, viruses including SARS-CoV-2 have evolved diverse mechanisms to not only overcome autophagy's antiviral pressure but also manipulate its machinery in order to enhance viral replication and propagation. Here, we discuss our current knowledge on the impact that autophagy exerts on SARS-CoV-2 replication, as well as the different counteracting measures that this virus has developed to manipulate autophagy's complex machinery. Some of the elements regarding this interplay may become future therapeutic targets in the fight against SARS-CoV-2.
2023-07-12 2023 other review-article; Review; Journal Article abstract-available 10.1128/mbio.01020-23 Bidirectional interplay between SARS-CoV-2 and autophagy. Zhou H, Hu Z, Castro-Gonzalez S. mBio. 2023; 14 (4)
The most exposed regions of SARS-CoV-2 structural proteins are subject to strong positive selection and gene overlap may locally modify this behavior.
Rubio A, de Toro M, Pérez-Pulido AJ.
mSystems. 2024; 9 (1)
DOI: 10.1128/msystems.00713-23
The SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) pandemic that emerged in 2019 has been an unprecedented event in international science, as it has been possible to sequence millions of genomes, tracking their evolution very closely. This has enabled various types of secondary analyses of these genomes, including the measurement of their sequence selection pressure. In this work, we have been able to measure the selective pressure of all the described SARS-CoV-2 genes, even analyzed by sequence regions, and we show how this type of analysis allows us to separate the genes between those subject to positive selection (usually those that code for surface proteins or those exposed to the host immune system) and those subject to negative selection because they require greater conservation of their structure and function. We have also seen that when another gene with an overlapping reading frame appears within a gene sequence, the overlapping sequence between the two genes evolves under a stronger purifying selection than the average of the non-overlapping regions of the main gene. We propose this type of analysis as a useful tool for locating and analyzing all the genes of a viral genome when an adequate number of sequences are available.IMPORTANCEWe have analyzed the selection pressure of all severe acute respiratory syndrome coronavirus 2 genes by means of the nonsynonymous (Ka) to synonymous (Ks) substitution rate. We found that protein-coding genes are exposed to strong positive selection, especially in the regions of interaction with other molecules (host receptor and genome of the virus itself). However, overlapping coding regions are more protected and show negative selection. This suggests that this measure could be used to study viral gene function as well as overlapping genes.
2023-12-14 2023 other research-article; Journal Article abstract-available 10.1128/msystems.00713-23 The most exposed regions of SARS-CoV-2 structural proteins are subject to strong positive selection and gene overlap may locally modify this behavior. Rubio A, de Toro M, Pérez-Pulido AJ. mSystems. 2024; 9 (1)
SARS-CoV-2 remodels the landscape of small non-coding RNAs with infection time and symptom severity
Gomez G, Corell-Sierra J, Marquez-Molins J, Marqués M, [...], Rodrigo G.
Research Square; 2023.
DOI: 10.21203/rs.3.rs-3375685/v1
The COVID-19 pandemic caused by the novel coronavirus SARS-CoV-2 has significantly impacted global health, stressing the necessity of basic understanding of the host response to this viral infection. In this study, we investigated how SARS-CoV-2 remodels the landscape of small non-coding RNAs (sncRNA) from a large collection of nasopharyngeal swab samples taken at various time points from patients with distinct symptom severity. High-throughput RNA sequencing analysis revealed a global alteration of the sncRNA landscape, with abundance peaks related to species of 21-23 and 32-33 nucleotides. Principal component analysis successfully discriminated infected patients based on the sncRNA profiles. Host-derived sncRNAs, including microRNAs (miRNAs), transfer RNA-derived small RNAs (tsRNAs), and small nucleolar RNAs (sdRNAs) exhibited significant differential expression in infected patients compared to controls. Importantly, miRNA expression was predominantly down-regulated in response to SARS-CoV-2 infection, especially in patients with severe symptoms. Furthermore, we identified specific tsRNAs derived from Glu- and Gly-tRNAs as major altered elements upon infection, with 5’ tRNA halves being the most abundant species and suggesting their potential as biomarkers for viral presence and disease severity prediction. Additionally, down-regulation of C/D-box sdRNAs and altered expression of tyRNAs were observed in infected patients. These findings provide valuable insights into the host sncRNA response to SARS-CoV-2 infection and may contribute to the development of further diagnostic and therapeutic strategies in the clinic.
2023-09-28 2023 other Preprint abstract-available 10.21203/rs.3.rs-3375685/v1 SARS-CoV-2 remodels the landscape of small non-coding RNAs with infection time and symptom severity Gomez G, Corell-Sierra J, Marquez-Molins J, Marqués M, Montagud-Martínez R, Cebriá-Mendoza M, Cuevas J, Albert E, Navarro D, Rodrigo G. Research Square; 2023.
Mesenchymal Stem Cell-Based Therapies in the Post-Acute Neurological COVID Syndrome: Current Landscape and Opportunities.
León-Moreno LC, Reza-Zaldívar EE, Hernández-Sapiéns MA, Villafaña-Estarrón E, [...], Canales-Aguirre AA.
Biomolecules. 2023; 14 (1)
DOI: 10.3390/biom14010008
One of the main concerns related to SARS-CoV-2 infection is the symptoms that could be developed by survivors, known as long COVID, a syndrome characterized by persistent symptoms beyond the acute phase of the infection. This syndrome has emerged as a complex and debilitating condition with a diverse range of manifestations affecting multiple organ systems. It is increasingly recognized for affecting the Central Nervous System, in which one of the most prevalent manifestations is cognitive impairment. The search for effective therapeutic interventions has led to growing interest in Mesenchymal Stem Cell (MSC)-based therapies due to their immunomodulatory, anti-inflammatory, and tissue regenerative properties. This review provides a comprehensive analysis of the current understanding and potential applications of MSC-based interventions in the context of post-acute neurological COVID-19 syndrome, exploring the underlying mechanisms by which MSCs exert their effects on neuroinflammation, neuroprotection, and neural tissue repair. Moreover, we discuss the challenges and considerations specific to employing MSC-based therapies, including optimal delivery methods, and functional treatment enhancements.
2023-12-20 2023 other review-article; Review; Journal Article abstract-available 10.3390/biom14010008 Mesenchymal Stem Cell-Based Therapies in the Post-Acute Neurological COVID Syndrome: Current Landscape and Opportunities. León-Moreno LC, Reza-Zaldívar EE, Hernández-Sapiéns MA, Villafaña-Estarrón E, García-Martin M, Ojeda-Hernández DD, Matias-Guiu JA, Gomez-Pinedo U, Matias-Guiu J, Canales-Aguirre AA. Biomolecules. 2023; 14 (1)
Molecular Evolution of SARS-CoV-2 during the COVID-19 Pandemic.
González-Vázquez LD, Arenas M.
Genes (Basel). 2023; 14 (2)
DOI: 10.3390/genes14020407
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) produced diverse molecular variants during its recent expansion in humans that caused different transmissibility and severity of the associated disease as well as resistance to monoclonal antibodies and polyclonal sera, among other treatments. In order to understand the causes and consequences of the observed SARS-CoV-2 molecular diversity, a variety of recent studies investigated the molecular evolution of this virus during its expansion in humans. In general, this virus evolves with a moderate rate of evolution, in the order of 10-3-10-4 substitutions per site and per year, which presents continuous fluctuations over time. Despite its origin being frequently associated with recombination events between related coronaviruses, little evidence of recombination was detected, and it was mostly located in the spike coding region. Molecular adaptation is heterogeneous among SARS-CoV-2 genes. Although most of the genes evolved under purifying selection, several genes showed genetic signatures of diversifying selection, including a number of positively selected sites that affect proteins relevant for the virus replication. Here, we review current knowledge about the molecular evolution of SARS-CoV-2 in humans, including the emergence and establishment of variants of concern. We also clarify relationships between the nomenclatures of SARS-CoV-2 lineages. We conclude that the molecular evolution of this virus should be monitored over time for predicting relevant phenotypic consequences and designing future efficient treatments.
2023-02-04 2023 other Research Support, Non-U.S. Gov't; review-article; Review; Journal Article abstract-available 10.3390/genes14020407 Molecular Evolution of SARS-CoV-2 during the COVID-19 Pandemic. González-Vázquez LD, Arenas M. Genes (Basel). 2023; 14 (2)
General approach to delivery and resuscitation of newborn infants from mothers at risk or proven COVID-19.
Aguar-Carrascosa M, Fernández-Colomer B, Renau MI, Iriondo-Sanz M, [...], Vento M.
Semin Fetal Neonatal Med. 2023; 28 (2)
DOI: 10.1016/j.siny.2023.101432
2023-03-30 2023 other Research Support, Non-U.S. Gov't; review-article; Review; Journal Article 10.1016/j.siny.2023.101432 General approach to delivery and resuscitation of newborn infants from mothers at risk or proven COVID-19. Aguar-Carrascosa M, Fernández-Colomer B, Renau MI, Iriondo-Sanz M, Cernada-Badía M, Vento M. Semin Fetal Neonatal Med. 2023; 28 (2)
SARS-CoV-2 Mac1 is required for IFN antagonism and efficient virus replication in cell culture and in mice.
Alhammad YM, Parthasarathy S, Ghimire R, Kerr CM, [...], Fehr AR.
Proc Natl Acad Sci U S A. 2023; 120 (35)
DOI: 10.1073/pnas.2302083120
Several coronavirus (CoV) encoded proteins are being evaluated as targets for antiviral therapies for COVID-19. Included in these drug targets is the conserved macrodomain, or Mac1, an ADP-ribosylhydrolase and ADP-ribose binding protein encoded as a small domain at the N terminus of nonstructural protein 3. Utilizing point mutant recombinant viruses, Mac1 was shown to be critical for both murine hepatitis virus (MHV) and severe acute respiratory syndrome (SARS)-CoV virulence. However, as a potential drug target, it is imperative to understand how a complete Mac1 deletion impacts the replication and pathogenesis of different CoVs. To this end, we created recombinant bacterial artificial chromosomes (BACs) containing complete Mac1 deletions (ΔMac1) in MHV, MERS-CoV, and SARS-CoV-2. While we were unable to recover infectious virus from MHV or MERS-CoV ΔMac1 BACs, SARS-CoV-2 ΔMac1 was readily recovered from BAC transfection, indicating a stark difference in the requirement for Mac1 between different CoVs. Furthermore, SARS-CoV-2 ΔMac1 replicated at or near wild-type levels in multiple cell lines susceptible to infection. However, in a mouse model of severe infection, ΔMac1 was quickly cleared causing minimal pathology without any morbidity. ΔMac1 SARS-CoV-2 induced increased levels of interferon (IFN) and IFN-stimulated gene expression in cell culture and mice, indicating that Mac1 blocks IFN responses which may contribute to its attenuation. ΔMac1 infection also led to a stark reduction in inflammatory monocytes and neutrophils. These results demonstrate that Mac1 only minimally impacts SARS-CoV-2 replication, unlike MHV and MERS-CoV, but is required for SARS-CoV-2 pathogenesis and is a unique antiviral drug target.
2023-08-22 2023 other Research Support, Non-U.S. Gov't; research-article; Research Support, U.S. Gov't, Non-P.H.S.; Journal Article; Research Support, N.I.H., Extramural abstract-available 10.1073/pnas.2302083120 SARS-CoV-2 Mac1 is required for IFN antagonism and efficient virus replication in cell culture and in mice. Alhammad YM, Parthasarathy S, Ghimire R, Kerr CM, O'Connor JJ, Pfannenstiel JJ, Chanda D, Miller CA, Baumlin N, Salathe M, Unckless RL, Zuñiga S, Enjuanes L, More S, Channappanavar R, Fehr AR. Proc Natl Acad Sci U S A. 2023; 120 (35)
Gag Virus-like Particles Functionalized with SARS-CoV-2 Variants: Generation, Characterization and Recognition by COVID-19 Convalescent Patients' Sera.
Boix-Besora A, Gòdia F, Cervera L.
Vaccines (Basel). 2023; 11 (11)
DOI: 10.3390/vaccines11111641
The robustness, safety, versatility, and high immunogenicity of virus-like particles (VLPs) make them a promising approach for the generation of vaccines against a broad range of pathogens. VLPs are recombinant macromolecular structures that closely mimic the native conformation of viruses without carrying viral genetic material. Particularly, HIV-1 Gag-based VLPs are a suitable platform for the presentation of the SARS-CoV-2 Spike (S) protein on their surface. In this context, this work studies the effect of different rationally engineered mutations of the S protein to improve some of its characteristics. The studied variants harbored mutations such as proline substitutions for S stabilization, D614G from the early dominant pandemic form, the elimination of the S1/S2 furin cleavage site to improve S homogeneity, the suppression of a retention motif to favor its membrane localization, and cysteine substitutions to increase its immunogenicity and avoid potential undesired antibody-dependent enhancement (ADE) effects. The influence of the mutations on VLP expression was studied, as well as their immunogenic potential, by testing the recognition of the generated VLP variants by COVID-19 convalescent patients' sera. The results of this work are conceived to give insights on the selection of S protein candidates for their use as immunogens and to showcase the potential of VLPs as carriers for antigen presentation.
2023-10-26 2023 other research-article; Journal Article abstract-available 10.3390/vaccines11111641 Gag Virus-like Particles Functionalized with SARS-CoV-2 Variants: Generation, Characterization and Recognition by COVID-19 Convalescent Patients' Sera. Boix-Besora A, Gòdia F, Cervera L. Vaccines (Basel). 2023; 11 (11)
Anti-SARS-CoV-2-specific antibodies in human breast milk following SARS-CoV-2 infection during pregnancy: a prospective cohort study.
Fernández-Buhigas I, Rayo N, Silos JC, Serrano B, [...], Poon LC.
Int Breastfeed J. 2024; 19 (1)
DOI: 10.1186/s13006-023-00605-w

Background

While the presence of SARS-CoV-2 in human breast milk is contentious, anti-SARS-CoV-2 antibodies have been consistently detected in human breast milk. However, it is uncertain when and how long the antibodies are present.

Methods

This was a prospective cohort study including all consecutive pregnant women with confirmed SARS-CoV-2 infection during pregnancy, recruited at six maternity units in Spain and Hong Kong from March 2020 to March 2021. Colostrum (day of birth until day 4 postpartum) and mature milk (day 7 postpartum until 6 weeks postpartum) were prospectively collected, and paired maternal blood samples were also collected. Colostrum samples were tested with rRT-PCR-SARS-CoV-2, and skimmed acellular milk and maternal sera were tested against SARS-CoV-2 specific immunoglobulin M, A, and G reactive to receptor binding domain of SARS-CoV-2 spike protein 1 to determine the presence of immunoglobulins. Then, we examined how each immunoglobulin type in the colostrum was related to the time of infection by logistic regression analysis, the concordance between these immunoglobulins in the colostrum, maternal serum, and mature milk by Cohen's kappa statistic, and the relationship between immunoglobulin levels in mature milk and colostrum with McNemar.

Results

One hundred eighty-seven pregnant women with confirmed SARS-CoV-2 infection during pregnancy or childbirth were recruited and donated the milk and blood samples. No SARS-CoV-2 was found in the human breast milk. Immunoglobulin A, G, and M were present in 129/162 (79·6%), 5/163 (3·1%), and 15/76 (19·7%) colostrum samples and in 17/62 (27·42%), 2/62 (3·23%) and 2/62 (3·23%) mature milk samples, respectively. Immunoglobulin A was the predominant immunoglobulin found in breast milk, and its levels were significantly higher in the colostrum than in the mature milk (p-value < 0.001). We did not find that the presence of immunoglobulins in the colostrum was associated with their presence in maternal, the severity of the disease, or the time when the infection had occurred.

Conclusions

Since anti-SARS-CoV-2 antibodies are found in the colostrum irrespective of the time of infection during pregnancy, but the virus itself is not detected in human breast milk, our study found no indications to withhold breastfeeding, taking contact precautions when there is active disease.
2024-01-18 2024 other research-article; Journal Article abstract-available 10.1186/s13006-023-00605-w Anti-SARS-CoV-2-specific antibodies in human breast milk following SARS-CoV-2 infection during pregnancy: a prospective cohort study. Fernández-Buhigas I, Rayo N, Silos JC, Serrano B, Ocón-Hernández O, Leung BW, Delgado JL, Fernández DS, Valle S, De Miguel L, Silgado A, Tanoira RP, Rolle V, Santacruz B, Gil MM, Poon LC. Int Breastfeed J. 2024; 19 (1)
Diversity of immune responses in children highly exposed to SARS-CoV-2.
Úbeda M, Maza MDC, Delgado P, Horndler L, [...], Fresno M.
Front Immunol. 2023; 14
DOI: 10.3389/fimmu.2023.1105237

Background

Children are less susceptible than adults to symptomatic COVID-19 infection, but very few studies addressed their underlying cause. Moreover, very few studies analyzed why children highly exposed to the virus remain uninfected.

Methods

We analyzed the serum levels of ACE2, angiotensin II, anti-spike and anti-N antibodies, cytokine profiles, and virus neutralization in a cohort of children at high risk of viral exposure, cohabiting with infected close relatives during the lockdown in Spain.

Results

We analyzed 40 children who were highly exposed to the virus since they lived with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-infected relatives during the lockdown for several months without taking preventive measures. Of those, 26 reported mild or very mild symptoms. The induced immune response to the virus was analyzed 3 months after the household infection. Surprisingly, only 15 children had IgG anti-S (IgG+) determined by a sensitive method indicative of a past infection. The rest, negative for IgG anti-N or S in various tests, could be further subdivided, according to IgM antibodies, into those having IgM anti-S and IgM anti-N (IgG-IgMhigh) and those having only IgM anti-N (IgG-IgMlow). Interestingly, those two subgroups of children with IgM antibodies have strikingly different patterns of cytokines. The IgMhigh group had significantly higher IFN-α2 and IFN-γ levels as well as IL-10 and GM-CSF than the IgMlow group. In contrast, the IgMlow group had low levels of ACE2 in the serum. Both groups have a weaker but significant capacity to neutralize the virus in the serum than the IgG+ group. Two children were negative in all immunological antibody tests.

Conclusions

A significant proportion of children highly exposed to SARS-CoV-2 did not develop a classical adaptive immune response, defined by the production of IgG, despite being in close contact with infected relatives. A large proportion of those children show immunological signs compatible with innate immune responses (as secretion of natural antibodies and cytokines), and others displayed very low levels of the viral receptor ACE2 that may have protected them from the virus spreading in the body despite high and constant viral exposure.
2023-03-03 2023 other Research Support, Non-U.S. Gov't; research-article; Journal Article abstract-available 10.3389/fimmu.2023.1105237 Diversity of immune responses in children highly exposed to SARS-CoV-2. Úbeda M, Maza MDC, Delgado P, Horndler L, Abia D, García-Bermejo L, Serrano-Villar S, Calvo C, Bastolla U, Sainz T, Fresno M. Front Immunol. 2023; 14
A retrospective study of SARS-CoV-2 seroprevalence in dogs and cats in the Community of Madrid, Spain.
Sánchez-Morales L, Sánchez-Vizcaíno JM, Domínguez L, Barroso-Arévalo S.
Front Microbiol. 2023; 14
DOI: 10.3389/fmicb.2023.1264172
To date, susceptibility to SARS-CoV-2 infection in domestic animals including cats and dogs has been described. However, it is important to carry out passive surveillance of these animals to be aware of any changes in the outcomes of the disease in these species that may occur. In this study, we have performed a retrospective study in which we analyzed sera (n = 1,640) from random animals: dogs (n = 1,381) and cats (n = 259) belonging to both homes (n = 1,533) and animal protection centers (n = 107) in the Community of Madrid, Spain. Neutralizing antibodies were evaluated between November 2021 and May 2022 using a surrogate ELISA kit to determine the seroprevalence. Based on the results obtained, a few animals (both cats and dogs) presented neutralizing antibodies to SARS-CoV-2 (2.3%), all of them from private owners. However, the seroprevalence in cats (4.6%) resulted to be almost twice as much as in dogs (1.9%) which reinforces that cats' susceptibility to the infection seems higher than in the case of dogs, maybe due to the lower ACE2 expression of the dogs in the respiratory tract. These findings also confirm that the probability of infection is considerably higher in domestic animals in close contact with infected owners, compared to animals living in animal shelters whose contact with humans is markedly lower.
2023-10-05 2023 other research-article; Journal Article abstract-available 10.3389/fmicb.2023.1264172 A retrospective study of SARS-CoV-2 seroprevalence in dogs and cats in the Community of Madrid, Spain. Sánchez-Morales L, Sánchez-Vizcaíno JM, Domínguez L, Barroso-Arévalo S. Front Microbiol. 2023; 14
Vaccinia Virus Strain MVA Expressing a Prefusion-Stabilized SARS-CoV-2 Spike Glycoprotein Induces Robust Protection and Prevents Brain Infection in Mouse and Hamster Models.
Lorenzo MM, Marín-López A, Chiem K, Jimenez-Cabello L, [...], Blasco R.
Vaccines (Basel). 2023; 11 (5)
DOI: 10.3390/vaccines11051006
The COVID-19 pandemic has underscored the importance of swift responses and the necessity of dependable technologies for vaccine development. Our team previously developed a fast cloning system for the modified vaccinia virus Ankara (MVA) vaccine platform. In this study, we reported on the construction and preclinical testing of a recombinant MVA vaccine obtained using this system. We obtained recombinant MVA expressing the unmodified full-length SARS-CoV-2 spike (S) protein containing the D614G amino-acid substitution (MVA-Sdg) and a version expressing a modified S protein containing amino-acid substitutions designed to stabilize the protein a in a pre-fusion conformation (MVA-Spf). S protein expressed by MVA-Sdg was found to be expressed and was correctly processed and transported to the cell surface, where it efficiently produced cell-cell fusion. Version Spf, however, was not proteolytically processed, and despite being transported to the plasma membrane, it failed to induce cell-cell fusion. We assessed both vaccine candidates in prime-boost regimens in the susceptible transgenic K18-human angiotensin-converting enzyme 2 (K18-hACE2) in mice and in golden Syrian hamsters. Robust immunity and protection from disease was induced with either vaccine in both animal models. Remarkably, the MVA-Spf vaccine candidate produced higher levels of antibodies, a stronger T cell response, and a higher degree of protection from challenge. In addition, the level of SARS-CoV-2 in the brain of MVA-Spf inoculated mice was decreased to undetectable levels. Those results add to our current experience and range of vaccine vectors and technologies for developing a safe and effective COVID-19 vaccine.
2023-05-21 2023 other research-article; Journal Article abstract-available 10.3390/vaccines11051006 Vaccinia Virus Strain MVA Expressing a Prefusion-Stabilized SARS-CoV-2 Spike Glycoprotein Induces Robust Protection and Prevents Brain Infection in Mouse and Hamster Models. Lorenzo MM, Marín-López A, Chiem K, Jimenez-Cabello L, Ullah I, Utrilla-Trigo S, Calvo-Pinilla E, Lorenzo G, Moreno S, Ye C, Park JG, Matía A, Brun A, Sánchez-Puig JM, Nogales A, Mothes W, Uchil PD, Kumar P, Ortego J, Fikrig E, Martinez-Sobrido L, Blasco R. Vaccines (Basel). 2023; 11 (5)
Association between soluble angiotensin-converting enzyme 2 in saliva and SARS-CoV-2 infection: a cross-sectional study.
Bru S, Brotons P, Jordan I, Alsina L, [...], Muñoz-Almagro C.
Sci Rep. 2023; 13 (1)
DOI: 10.1038/s41598-023-31911-2
This study aimed to investigate the association between saliva soluble angiotensin-converting enzyme 2 (sACE2) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children and adults. We selected a convenience sample of adults with post-acute SARS-CoV-2 infection and their household children living in quarantined family households of the metropolitan Barcelona region (Spain) during the spring 2020 pandemic national lockdown. Participants were tested for saliva sACE2 quantification by western blot and nasopharyngeal SARS-CoV-2 RT-PCR detection. A total of 161 saliva samples [82 (50.9%) from children; 79 (49.1%) from females] yielded valid western blot and RT-PCR results. Saliva sACE2 was detected in 79 (96.3%) children and 76 (96.2%) convalescent adults. Twenty (24.4%) children and 20 (25.3%) convalescent adults were positive for SARS-CoV-2 in nasopharynx by RT-PCR. SARS-CoV-2 RT-PCR-negative children had a significantly higher mean proportional level of saliva sACE2 (0.540 × 10-3%) than RT-PCR-positive children (0.192 × 10-3%, p < 0.001) and convalescent adults (0.173 × 10-3%, p < 0.001). In conclusion, children negative for nasopharyngeal SARS-CoV-2 RT-PCR appear to exhibit a higher concentration of saliva sACE2 than SARS-CoV-2 RT-PCR-positive children and convalescent adults. Release of adequate levels of sACE2 in saliva could play a protective role against SARS-CoV-2.
2023-04-12 2023 other Research Support, Non-U.S. Gov't; research-article; Journal Article abstract-available 10.1038/s41598-023-31911-2 Association between soluble angiotensin-converting enzyme 2 in saliva and SARS-CoV-2 infection: a cross-sectional study. Bru S, Brotons P, Jordan I, Alsina L, Henares D, Carballar R, de Sevilla MF, Barrabeig I, Fumado V, Baro B, Martínez-Láinez JM, Garcia-Garcia JJ, Bassat Q, Balaguer A, Clotet J, Launes C, Muñoz-Almagro C. Sci Rep. 2023; 13 (1)
Monitoring SARS-CoV-2 genetic variability: A post-market surveillance workflow for combined bioinformatic and laboratory evaluation of commercial RT-PCR assay performance.
Kosińska-Selbi B, Kowalczyk J, Pierscińska J, Wełeszczuk J, [...], Blacha A.
PLoS One. 2024; 19 (1)
DOI: 10.1371/journal.pone.0294271

Objective

The speed at which Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is mutating has made it necessary to frequently assess how these genomic changes impact the performance of diagnostic real-time polymerase chain reaction (RT-PCR) assays. Herein, we describe a generic three-step workflow to assess the effect of genomic mutations on inclusivity and sensitivity of RT-PCR assays.

Methods

Sequences collected from the Global Initiative on Sharing All Influenza Data (GISAID) were mapped to a SARS-CoV-2 reference genome to evaluate the position and prevalence of mismatches in the oligonucleotide-binding sites of the QIAstat-Dx, an RT-PCR panel designed to detect SARS-CoV-2. The frequency of mutations and their impact on melting temperature were assessed, and sequences flagged by risk-based criteria were examined in vitro.

Results

Out of 8,900,393 SARS-CoV-2 genome sequences analyzed, only 173 (0.0019%) genomes contained potentially critical mutations for the QIAstat-Dx; follow-up in-vitro testing confirmed no impact on the assays' performance.

Conclusions

The current study demonstrates that SARS-CoV-2 genetic variants do not affect the performance of the QIAstat-Dx device. It is recommended that manufacturers incorporate this workflow into obligatory post-marketing surveillance activities, as this approach could potentially enhance genetic monitoring of their product.
2024-01-12 2024 other research-article; Journal Article abstract-available 10.1371/journal.pone.0294271 Monitoring SARS-CoV-2 genetic variability: A post-market surveillance workflow for combined bioinformatic and laboratory evaluation of commercial RT-PCR assay performance. Kosińska-Selbi B, Kowalczyk J, Pierscińska J, Wełeszczuk J, Peñarrubia L, Turner B, Pareja J, Porco R, Diaz-Hernandez R, Juanola-Falgarona M, Rey M, Manissero D, Blacha A. PLoS One. 2024; 19 (1)
COVID-19 in pregnant women: a systematic review and meta-analysis on the risk and prevalence of pregnancy loss.
van Baar JAC, Kostova EB, Allotey J, Thangaratinam S, [...], PregCOV-19 Living Systematic Review Consortium .
Hum Reprod Update. 2024; 30 (2)
DOI: 10.1093/humupd/dmad030

Background

Pregnant women infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are more likely to experience preterm birth and their neonates are more likely to be stillborn or admitted to a neonatal unit. The World Health Organization declared in May 2023 an end to the coronavirus disease 2019 (COVID-19) pandemic as a global health emergency. However, pregnant women are still becoming infected with SARS-CoV-2 and there is limited information available regarding the effect of SARS-CoV-2 infection in early pregnancy on pregnancy outcomes.

Objective and rationale

We conducted this systematic review to determine the prevalence of early pregnancy loss in women with SARS-Cov-2 infection and compare the risk to pregnant women without SARS-CoV-2 infection.

Search methods

Our systematic review is based on a prospectively registered protocol. The search of PregCov19 consortium was supplemented with an extra electronic search specifically on pregnancy loss in pregnant women infected with SARS-CoV-2 up to 10 March 2023 in PubMed, Google Scholar, and LitCovid. We included retrospective and prospective studies of pregnant women with SARS-CoV-2 infection, provided that they contained information on pregnancy losses in the first and/or second trimester. Primary outcome was miscarriage defined as a pregnancy loss before 20 weeks of gestation, however, studies that reported loss up to 22 or 24 weeks were also included. Additionally, we report on studies that defined the pregnancy loss to occur at the first and/or second trimester of pregnancy without specifying gestational age, and for second trimester miscarriage only when the study presented stillbirths and/or foetal losses separately from miscarriages. Data were stratified into first and second trimester. Secondary outcomes were ectopic pregnancy (any extra-uterine pregnancy), and termination of pregnancy. At least three researchers independently extracted the data and assessed study quality. We calculated odds ratios (OR) and risk differences (RDs) with corresponding 95% CI and pooled the data using random effects meta-analysis. To estimate risk prevalence, we performed meta-analysis on proportions. Heterogeneity was assessed by I2.

Outcomes

We included 120 studies comprising a total of 168 444 pregnant women with SARS-CoV-2 infection; of which 18 233 women were in their first or second trimester of pregnancy. Evidence level was considered to be of low to moderate certainty, mostly owing to selection bias. We did not find evidence of an association between SARS-CoV-2 infection and miscarriage (OR 1.10, 95% CI 0.81-1.48; I2 = 0.0%; RD 0.0012, 95% CI -0.0103 to 0.0127; I2 = 0%; 9 studies, 4439 women). Miscarriage occurred in 9.9% (95% CI 6.2-14.0%; I2 = 68%; 46 studies, 1797 women) of the women with SARS CoV-2 infection in their first trimester and in 1.2% (95% CI 0.3-2.4%; I2 = 34%; 33 studies; 3159 women) in the second trimester. The proportion of ectopic pregnancies in women with SARS-CoV-2 infection was 1.4% (95% CI 0.02-4.2%; I2 = 66%; 14 studies, 950 women). Termination of pregnancy occurred in 0.6% of the women (95% CI 0.01-1.6%; I2 = 79%; 39 studies; 1166 women).

Wider implications

Our study found no indication that SARS-CoV-2 infection in the first or second trimester increases the risk of miscarriages. To provide better risk estimates, well-designed studies are needed that include pregnant women with and without SARS-CoV-2 infection at conception and early pregnancy and consider the association of clinical manifestation and severity of SARS-CoV-2 infection with pregnancy loss, as well as potential confounding factors such as previous pregnancy loss. For clinical practice, pregnant women should still be advised to take precautions to avoid risk of SARS-CoV-2 exposure and receive SARS-CoV-2 vaccination.
2024-03-01 2024 other Meta-Analysis; Systematic Review; review-article; Journal Article abstract-available 10.1093/humupd/dmad030 COVID-19 in pregnant women: a systematic review and meta-analysis on the risk and prevalence of pregnancy loss. van Baar JAC, Kostova EB, Allotey J, Thangaratinam S, Zamora JR, Bonet M, Kim CR, Mofenson LM, Kunst H, Khalil A, van Leeuwen E, Keijzer J, Strikwerda M, Clark B, Verschuuren M, Coomarasamy A, Goddijn M, van Wely M, PregCOV-19 Living Systematic Review Consortium . Hum Reprod Update. 2024; 30 (2)
Investigating the structural network underlying brain-immune interactions using combined histopathology and neuroimaging: a critical review for its relevance in acute and long COVID-19.
Kikinis Z, Castañeyra-Perdomo A, González-Mora JL, Rushmore RJ, [...], Makris N.
Front Psychiatry. 2024; 15
DOI: 10.3389/fpsyt.2024.1337888
Current views on immunity support the idea that immunity extends beyond defense functions and is tightly intertwined with several other fields of biology such as virology, microbiology, physiology and ecology. It is also critical for our understanding of autoimmunity and cancer, two topics of great biological relevance and for critical public health considerations such as disease prevention and treatment. Central to this review, the immune system is known to interact intimately with the nervous system and has been recently hypothesized to be involved not only in autonomic and limbic bio-behaviors but also in cognitive function. Herein we review the structural architecture of the brain network involved in immune response. Furthermore, we elaborate upon the implications of inflammatory processes affecting brain-immune interactions as reported recently in pathological conditions due to SARS-Cov-2 virus infection, namely in acute and post-acute COVID-19. Moreover, we discuss how current neuroimaging techniques combined with ad hoc clinical autopsies and histopathological analyses could critically affect the validity of clinical translation in studies of human brain-immune interactions using neuroimaging. Advances in our understanding of brain-immune interactions are expected to translate into novel therapeutic avenues in a vast array of domains including cancer, autoimmune diseases or viral infections such as in acute and post-acute or Long COVID-19.
2024-03-25 2024 other review-article; Review; Journal Article abstract-available 10.3389/fpsyt.2024.1337888 Investigating the structural network underlying brain-immune interactions using combined histopathology and neuroimaging: a critical review for its relevance in acute and long COVID-19. Kikinis Z, Castañeyra-Perdomo A, González-Mora JL, Rushmore RJ, Toppa PH, Haggerty K, Papadimitriou G, Rathi Y, Kubicki M, Kikinis R, Heller C, Yeterian E, Besteher B, Pallanti S, Makris N. Front Psychiatry. 2024; 15
A review of SARS-CoV-2 drug repurposing: databases and machine learning models.
Elkashlan M, Ahmad RM, Hajar M, Al Jasmi F, [...], Mohamad MS.
Front Pharmacol. 2023; 14
DOI: 10.3389/fphar.2023.1182465
The emergence of Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) posed a serious worldwide threat and emphasized the urgency to find efficient solutions to combat the spread of the virus. Drug repurposing has attracted more attention than traditional approaches due to its potential for a time- and cost-effective discovery of new applications for the existing FDA-approved drugs. Given the reported success of machine learning (ML) in virtual drug screening, it is warranted as a promising approach to identify potential SARS-CoV-2 inhibitors. The implementation of ML in drug repurposing requires the presence of reliable digital databases for the extraction of the data of interest. Numerous databases archive research data from studies so that it can be used for different purposes. This article reviews two aspects: the frequently used databases in ML-based drug repurposing studies for SARS-CoV-2, and the recent ML models that have been developed for the prospective prediction of potential inhibitors against the new virus. Both types of ML models, Deep Learning models and conventional ML models, are reviewed in terms of introduction, methodology, and its recent applications in the prospective predictions of SARS-CoV-2 inhibitors. Furthermore, the features and limitations of the databases are provided to guide researchers in choosing suitable databases according to their research interests.
2023-08-04 2023 other review-article; Review; Journal Article abstract-available 10.3389/fphar.2023.1182465 A review of SARS-CoV-2 drug repurposing: databases and machine learning models. Elkashlan M, Ahmad RM, Hajar M, Al Jasmi F, Corchado JM, Nasarudin NA, Mohamad MS. Front Pharmacol. 2023; 14
COVID-19 and Pregnancy: A Dangerous Mix for Bone Turnover and Metabolism Biomarkers in Placenta and Colostrum.
Diaz-Castro J, Toledano JM, Sanchez-Romero J, Aguilar AC, [...], Ochoa JJ.
J Clin Med. 2024; 13 (7)
DOI: 10.3390/jcm13072124
Background: In pregnant women, COVID-19 can alter the metabolic environment, cell metabolism, and oxygen supply of trophoblastic cells and, therefore, have a negative influence on essential mechanisms of fetal development. The purpose of this study was to investigate, for the first time, the effects of COVID-19 infection during pregnancy with regard to the bone turnover and endocrine function of several metabolic biomarkers in colostrum and placenta. Methods: One hundred and twenty-four pregnant mothers were recruited from three hospitals between June 2020 and August 2021 and assigned to two groups: Control group and COVID-19 group. Metabolism biomarkers were addressed in placental tissue and colostrum. Results: Lipocalin-2 and resistin levels were higher in the placenta, revealing an underlying pro-inflammatory status in the gestation period for mothers suffering from COVID-19; a decrease in GLP-1 and leptin was also observed in this group. As for adiponectin, resistin, and insulin, their concentrations showed an increase; a decrease in GLP-1, leptin, and PYY was also reported in the colostrum of mothers suffering from COVID-19 compared with the control group. Conclusions: As for bone turnover, placental samples from mothers with COVID-19 showed lower levels of OPG, while DKK-1 increased compared with the control group. Colostrum samples showed higher levels of OPG, SOST, and PTH in the COVID-19 group, a fact that could have noteworthy implications for energy metabolism, fetal skeletal development, and postnatal bone density and mineralization. Further research is needed to explain the pathogenic mechanism of COVID-19 that may affect pregnancy, so as to assess the short-term and long-term outcomes in infants' health.
2024-04-06 2024 other research-article; Journal Article abstract-available 10.3390/jcm13072124 COVID-19 and Pregnancy: A Dangerous Mix for Bone Turnover and Metabolism Biomarkers in Placenta and Colostrum. Diaz-Castro J, Toledano JM, Sanchez-Romero J, Aguilar AC, Martín-Alvarez E, Puche-Juarez M, Moreno-Fernandez J, Pinar-Gonzalez M, Prados S, Carrillo MP, Ruiz-Duran S, De Paco Matallana C, Ochoa JJ. J Clin Med. 2024; 13 (7)
The role of DC-SIGN as a trans-receptor in infection by MERS-CoV.
Labiod N, Luczkowiak J, Tapia MM, Lasala F, [...], Delgado R.
Front Cell Infect Microbiol. 2023; 13
DOI: 10.3389/fcimb.2023.1177270
DC-SIGN is a C-type lectin expressed in myeloid cells such as immature dendritic cells and macrophages. Through glycan recognition in viral envelope glycoproteins, DC-SIGN has been shown to act as a receptor for a number of viral agents such as HIV, Ebola virus, SARS-CoV, and SARS-CoV-2. Using a system of Vesicular Stomatitis Virus pseudotyped with MERS-CoV spike protein, here, we show that DC-SIGN is partially responsible for MERS-CoV infection of dendritic cells and that DC-SIGN efficiently mediates trans-infection of MERS-CoV from dendritic cells to susceptible cells, indicating a potential role of DC-SIGN in MERS-CoV dissemination and pathogenesis.
2023-09-21 2023 other Research Support, Non-U.S. Gov't; research-article; Journal Article abstract-available 10.3389/fcimb.2023.1177270 The role of DC-SIGN as a trans-receptor in infection by MERS-CoV. Labiod N, Luczkowiak J, Tapia MM, Lasala F, Delgado R. Front Cell Infect Microbiol. 2023; 13
P53-Independent G1-Cell Cycle Arrest Increases SARS-CoV-2 RNA Replication.
Husser C, Kwon H, Andersson K, Appelberg S, [...], Monteil VM.
Microorganisms. 2024; 12 (3)
DOI: 10.3390/microorganisms12030443
While having already killed more than 7 million of people worldwide in 4 years, SARS-CoV-2, the etiological agent of COVID-19, is still circulating and evolving. Understanding the pathogenesis of the virus is of capital importance. It was shown that in vitro and in vivo infection with SARS-CoV-2 can lead to cell cycle arrest but the effect of the cell cycle arrest on the virus infection and the associated mechanisms are still unclear. By stopping cells in the G1 phase as well as targeting several pathways involved using inhibitors and small interfering RNAs, we were able to determine that the cell cycle arrest in the late G1 is beneficial for SARS-CoV-2 replication. This cell cycle arrest is independent of p53 but is dependent on the CDC25A-CDK2/cyclin E pathway. These data give a new understanding in SARS-CoV-2 pathogenesis and highlight some possible targets for the development of novel therapeutic approaches.
2024-02-22 2024 other research-article; Journal Article abstract-available 10.3390/microorganisms12030443 P53-Independent G1-Cell Cycle Arrest Increases SARS-CoV-2 RNA Replication. Husser C, Kwon H, Andersson K, Appelberg S, Montserrat N, Mirazimi A, Monteil VM. Microorganisms. 2024; 12 (3)
Temperature impacts SARS-CoV-2 spike fusogenicity and evolution.
Dufloo J, Sanjuán R.
mBio. 2024; 15 (4)
DOI: 10.1128/mbio.03360-23
SARS-CoV-2 infects both the upper and lower respiratory tracts, which are characterized by different temperatures (33°C and 37°C, respectively). In addition, fever is a common COVID-19 symptom. SARS-CoV-2 has been shown to replicate more efficiently at low temperatures, but the effect of temperature on different viral proteins remains poorly understood. Here, we investigate how temperature affects the SARS-CoV-2 spike function and evolution. We first observed that increasing temperature from 33°C to 37°C or 39°C increased spike-mediated cell-cell fusion. We then experimentally evolved a recombinant vesicular stomatitis virus expressing the SARS-CoV-2 spike at these different temperatures. We found that spike-mediated cell-cell fusion was maintained during evolution at 39°C but was lost in a high proportion of viruses that evolved at 33°C or 37°C. Consistently, sequencing of the spikes evolved at 33°C or 37°C revealed the accumulation of mutations around the furin cleavage site, a region that determines cell-cell fusion, whereas this did not occur in spikes evolved at 39°C. Finally, using site-directed mutagenesis, we found that disruption of the furin cleavage site had a temperature-dependent effect on spike-induced cell-cell fusion and viral fitness. Our results suggest that variations in body temperature may affect the activity and diversification of the SARS-CoV-2 spike.

Importance

When it infects humans, SARS-CoV-2 is exposed to different temperatures (e.g., replication site and fever). Temperature has been shown to strongly impact SARS-CoV-2 replication, but how it affects the activity and evolution of the spike protein remains poorly understood. Here, we first show that high temperatures increase the SARS-CoV-2 spike fusogenicity. Then, we demonstrate that the evolution of the spike activity and variants depends on temperature. Finally, we show that the functional effect of specific spike mutations is temperature-dependent. Overall, our results suggest that temperature may be a factor influencing the activity and adaptation of the SARS-CoV-2 spike in vivo, which will help understanding viral tropism, pathogenesis, and evolution.
2024-02-27 2024 other research-article; Journal Article abstract-available 10.1128/mbio.03360-23 Temperature impacts SARS-CoV-2 spike fusogenicity and evolution. Dufloo J, Sanjuán R. mBio. 2024; 15 (4)
Mechanisms of endothelial activation, hypercoagulation and thrombosis in COVID-19: a link with diabetes mellitus.
Valencia I, Lumpuy-Castillo J, Magalhaes G, Sánchez-Ferrer CF, [...], Peiró C.
Cardiovasc Diabetol. 2024; 23 (1)
DOI: 10.1186/s12933-023-02097-8
Early since the onset of the COVID-19 pandemic, the medical and scientific community were aware of extra respiratory actions of SARS-CoV-2 infection. Endothelitis, hypercoagulation, and hypofibrinolysis were identified in COVID-19 patients as subsequent responses of endothelial dysfunction. Activation of the endothelial barrier may increase the severity of the disease and contribute to long-COVID syndrome and post-COVID sequelae. Besides, it may cause alterations in primary, secondary, and tertiary hemostasis. Importantly, these responses have been highly decisive in the evolution of infected patients also diagnosed with diabetes mellitus (DM), who showed previous endothelial dysfunction. In this review, we provide an overview of the potential triggers of endothelial activation related to COVID-19 and COVID-19 under diabetic milieu. Several mechanisms are induced by both the viral particle itself and by the subsequent immune-defensive response (i.e., NF-κB/NLRP3 inflammasome pathway, vasoactive peptides, cytokine storm, NETosis, activation of the complement system). Alterations in coagulation mediators such as factor VIII, fibrin, tissue factor, the von Willebrand factor: ADAMST-13 ratio, and the kallikrein-kinin or plasminogen-plasmin systems have been reported. Moreover, an imbalance of thrombotic and thrombolytic (tPA, PAI-I, fibrinogen) factors favors hypercoagulation and hypofibrinolysis. In the context of DM, these mechanisms can be exacerbated leading to higher loss of hemostasis. However, a series of therapeutic strategies targeting the activated endothelium such as specific antibodies or inhibitors against thrombin, key cytokines, factor X, complement system, the kallikrein-kinin system or NETosis, might represent new opportunities to address this hypercoagulable state present in COVID-19 and DM. Antidiabetics may also ameliorate endothelial dysfunction, inflammation, and platelet aggregation. By improving the microvascular pathology in COVID-19 and post-COVID subjects, the associated comorbidities and the risk of mortality could be reduced.
2024-02-20 2024 other Research Support, Non-U.S. Gov't; review-article; Review; Journal Article abstract-available 10.1186/s12933-023-02097-8 Mechanisms of endothelial activation, hypercoagulation and thrombosis in COVID-19: a link with diabetes mellitus. Valencia I, Lumpuy-Castillo J, Magalhaes G, Sánchez-Ferrer CF, Lorenzo Ó, Peiró C. Cardiovasc Diabetol. 2024; 23 (1)
Vessel-on-a-Chip: A Powerful Tool for Investigating Endothelial COVID-19 Fingerprints.
Shevchuk O, Palii S, Pak A, Chantada N, [...], Álvarez E.
Cells. 2023; 12 (9)
DOI: 10.3390/cells12091297
Coronavirus disease (COVID-19) causes various vascular and blood-related reactions, including exacerbated responses. The role of endothelial cells in this acute response is remarkable and may remain important beyond the acute phase. As we move into a post-COVID-19 era (where most people have been or will be infected by the SARS-CoV-2 virus), it is crucial to define the vascular consequences of COVID-19, including the long-term effects on the cardiovascular system. Research is needed to determine whether chronic endothelial dysfunction following COVID-19 could lead to an increased risk of cardiovascular and thrombotic events. Endothelial dysfunction could also serve as a diagnostic and therapeutic target for post-COVID-19. This review covers these topics and examines the potential of emerging vessel-on-a-chip technology to address these needs. Vessel-on-a-chip would allow for the study of COVID-19 pathophysiology in endothelial cells, including the analysis of SARS-CoV-2 interactions with endothelial function, leukocyte recruitment, and platelet activation. "Personalization" could be implemented in the models through induced pluripotent stem cells, patient-specific characteristics, or genetic modified cells. Adaptation for massive testing under standardized protocols is now possible, so the chips could be incorporated for the personalized follow-up of the disease or its sequalae (long COVID) and for the research of new drugs against COVID-19.
2023-05-02 2023 other Research Support, Non-U.S. Gov't; review-article; Review; Journal Article abstract-available 10.3390/cells12091297 Vessel-on-a-Chip: A Powerful Tool for Investigating Endothelial COVID-19 Fingerprints. Shevchuk O, Palii S, Pak A, Chantada N, Seoane N, Korda M, Korda M, Campos-Toimil M, Álvarez E. Cells. 2023; 12 (9)
Specific Activation of T Cells by an ACE2-Based CAR-Like Receptor upon Recognition of SARS-CoV-2 Spike Protein.
Gonzalez-Garcia P, Muñoz-Miranda JP, Fernandez-Cisnal R, Olvera L, [...], Garcia-Cozar F.
Int J Mol Sci. 2023; 24 (8)
DOI: 10.3390/ijms24087641
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the causative agent of the Coronavirus Disease 2019 (COVID-19) pandemic, which is still a health issue worldwide mostly due to a high rate of contagiousness conferred by the high-affinity binding between cell viral receptors, Angiotensin-Converting Enzyme 2 (ACE2) and SARS-CoV-2 Spike protein. Therapies have been developed that rely on the use of antibodies or the induction of their production (vaccination), but despite vaccination being still largely protective, the efficacy of antibody-based therapies wanes with the advent of new viral variants. Chimeric Antigen Receptor (CAR) therapy has shown promise for tumors and has also been proposed for COVID-19 treatment, but as recognition of CARs still relies on antibody-derived sequences, they will still be hampered by the high evasion capacity of the virus. In this manuscript, we show the results from CAR-like constructs with a recognition domain based on the ACE2 viral receptor, whose ability to bind the virus will not wane, as Spike/ACE2 interaction is pivotal for viral entry. Moreover, we have developed a CAR construct based on an affinity-optimized ACE2 and showed that both wild-type and affinity-optimized ACE2 CARs drive activation of a T cell line in response to SARS-CoV-2 Spike protein expressed on a pulmonary cell line. Our work sets the stage for the development of CAR-like constructs against infectious agents that would not be affected by viral escape mutations and could be developed as soon as the receptor is identified.
2023-04-21 2023 fondo-covid research-article; Journal Article abstract-available 10.3390/ijms24087641 Specific Activation of T Cells by an ACE2-Based CAR-Like Receptor upon Recognition of SARS-CoV-2 Spike Protein. Gonzalez-Garcia P, Muñoz-Miranda JP, Fernandez-Cisnal R, Olvera L, Moares N, Gabucio A, Fernandez-Ponce C, Garcia-Cozar F. Int J Mol Sci. 2023; 24 (8)
SARS-CoV-2 Mac1 is required for IFN antagonism and efficient virus replication in mice
Alhammad YM, Parthasarathy S, Ghimire R, O’Connor JJ, [...], Fehr AR.
bioRxiv; 2023.
DOI: 10.1101/2023.04.06.535927

ABSTRACT

Several coronavirus (CoV) encoded proteins are being evaluated as targets for antiviral therapies for COVID-19. Included in this set of proteins is the conserved macrodomain, or Mac1, an ADP-ribosylhydrolase and ADP-ribose binding protein. Utilizing point mutant recombinant viruses, Mac1 was shown to be critical for both murine hepatitis virus (MHV) and severe acute respiratory syndrome (SARS)-CoV virulence. However, as a potential drug target, it is imperative to understand how a complete Mac1 deletion impacts the replication and pathogenesis of different CoVs. To this end, we created recombinant bacterial artificial chromosomes (BACs) containing complete Mac1 deletions (ΔMac1) in MHV, MERS-CoV, and SARS-CoV-2. While we were unable to recover infectious virus from MHV or MERS-CoV ΔMac1 BACs, SARS-CoV-2 ΔMac1 was readily recovered from BAC transfection, indicating a stark difference in the requirement for Mac1 between different CoVs. Furthermore, SARS-CoV-2 ΔMac1 replicated at or near wild-type levels in multiple cell lines susceptible to infection. However, in a mouse model of severe infection, ΔMac1 was quickly cleared causing minimal pathology without any morbidity. ΔMac1 SARS-CoV-2 induced increased levels of interferon (IFN) and interferon-stimulated gene (ISG) expression in cell culture and mice, indicating that Mac1 blocks IFN responses which may contribute to its attenuation. ΔMac1 infection also led to a stark reduction in inflammatory monocytes and neutrophils. These results demonstrate that Mac1 only minimally impacts SARS-CoV-2 replication, unlike MHV and MERS-CoV, but is required for SARS-CoV-2 pathogenesis and is a unique antiviral drug target.

SIGNIFICANCE

All CoVs, including SARS-CoV-2, encode for a conserved macrodomain (Mac1) that counters host ADP-ribosylation. Prior studies with SARS-CoV-1 and MHV found that Mac1 blocks IFN production and promotes CoV pathogenesis, which has prompted the development of SARS-CoV-2 Mac1 inhibitors. However, development of these compounds into antivirals requires that we understand how SARS-CoV-2 lacking Mac1 replicates and causes disease in vitro and in vivo . Here we found that SARS-CoV-2 containing a complete Mac1 deletion replicates normally in cell culture but induces an elevated IFN response, has reduced viral loads in vivo , and does not cause significant disease in mice. These results will provide a roadmap for testing Mac1 inhibitors, help identify Mac1 functions, and open additional avenues for coronavirus therapies.
2023-04-06 2023 other Preprint abstract-available 10.1101/2023.04.06.535927 SARS-CoV-2 Mac1 is required for IFN antagonism and efficient virus replication in mice Alhammad YM, Parthasarathy S, Ghimire R, O’Connor JJ, Kerr CM, Pfannenstiel JJ, Chanda D, Miller CA, Unckless RL, Zuniga S, Enjuanes L, More S, Channappanavar R, Fehr AR. bioRxiv; 2023.
Three-Dimensional Remodeling of SARS-CoV2-Infected Cells Revealed by Cryogenic Soft X-ray Tomography.
Castro V, Pérez-Berna AJ, Calvo G, Pereiro E, [...], Gastaminza P.
ACS Nano. 2023; 17 (22)
DOI: 10.1021/acsnano.3c07265
Plus-strand RNA viruses are proficient at remodeling host cell membranes for optimal viral genome replication and the production of infectious progeny. These ultrastructural alterations result in the formation of viral membranous organelles and may be observed by different imaging techniques, providing nanometric resolution. Guided by confocal and electron microscopy, this study describes the generation of wide-field volumes using cryogenic soft-X-ray tomography (cryo-SXT) on SARS-CoV-2-infected human lung adenocarcinoma cells. Confocal microscopy showed accumulation of double-stranded RNA (dsRNA) and nucleocapsid (N) protein in compact perinuclear structures, preferentially found around centrosomes at late stages of the infection. Transmission electron microscopy (TEM) showed accumulation of membranous structures in the vicinity of the infected cell nucleus, forming a viral replication organelle containing characteristic double-membrane vesicles and virus-like particles within larger vesicular structures. Cryo-SXT revealed viral replication organelles very similar to those observed by TEM but indicated that the vesicular organelle observed in TEM sections is indeed a vesiculo-tubular network that is enlarged and elongated at late stages of the infection. Overall, our data provide additional insight into the molecular architecture of the SARS-CoV-2 replication organelle.
2023-11-08 2023 other Research Support, Non-U.S. Gov't; research-article; Journal Article abstract-available 10.1021/acsnano.3c07265 Three-Dimensional Remodeling of SARS-CoV2-Infected Cells Revealed by Cryogenic Soft X-ray Tomography. Castro V, Pérez-Berna AJ, Calvo G, Pereiro E, Gastaminza P. ACS Nano. 2023; 17 (22)
Specific IgA, But Not IgG, in Human Milk From COVID-19-Infected Mothers Neutralizes SARS-CoV-2.
Macchiaverni P, Lloyd M, Masters L, Divakara N, [...], Verhasselt V.
Pediatr Infect Dis J. 2024; 43 (6)
DOI: 10.1097/inf.0000000000004291
This study highlights the importance of human milk in providing anti-severe acute respiratory syndrome coronavirus 2 immunity to newborns. The highest protective activity of human milk against COVID-19 was found in colostrum from infected mothers. Neutralizing activity was associated with high levels of specific IgA. Depletion of IgA, but not IgG, from milk samples completely abolished the ability of human milk to neutralize severe acute respiratory syndrome coronavirus 2.
2024-02-29 2024 other research-article; Journal Article abstract-available 10.1097/inf.0000000000004291 Specific IgA, But Not IgG, in Human Milk From COVID-19-Infected Mothers Neutralizes SARS-CoV-2. Macchiaverni P, Lloyd M, Masters L, Divakara N, Panta K, Imrie A, Sánchez-García L, Pellicer A, Rodriguez JM, Verhasselt V. Pediatr Infect Dis J. 2024; 43 (6)
Plasma of COVID-19 patients does not alter electrical resistance of human endothelial blood-brain barrierin vitro
Pociūtė A, Kriaučiūnaitė K, Kaušylė A, Zablockienė B, [...], Pivoriūnas A.
bioRxiv; 2023.
DOI: 10.1101/2023.09.28.559927
The pandemic of Coronavirus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) instigated the most serious global health crisis. Clinical presentation of COVID-19 frequently includes severe neurological and neuropsychiatric symptoms. However, it is presently unknown whether and to which extent pathological impairment of blood-brain barrier (BBB) contributes to the development of neuropathology during COVID-19 progression. In the present study we used human induced pluripotent stem cells-derived brain endothelial cells (iBECs) to study the effects of blood plasma derived from COVID-19 patients on the BBB integrity in vitro . We also performed a comprehensive analysis of the cytokine and chemokine profiles in the plasma of COVID-19 patients, healthy and recovered individuals. We found significantly increased levels of interferon γ-induced protein 10 kDa (IP-10), hepatocyte growth factor (HGF), and interleukin-18 (IL-18) in the plasma of COVID-19 patients. However, blood plasma from COVID-19 patients did not affect transendothelial electrical resistance (TEER) in iBEC monolayers. Our results demonstrate that COVID-19-associated blood plasma inflammatory factors do not impair BBB integrity directly and suggest that pathological remodelling of BBB during COVID-19 may occur through indirect mechanisms.
2023-09-29 2023 other Preprint abstract-available 10.1101/2023.09.28.559927 Plasma of COVID-19 patients does not alter electrical resistance of human endothelial blood-brain barrier<i>in vitro</i> Pociūtė A, Kriaučiūnaitė K, Kaušylė A, Zablockienė B, Alčauskas T, Jelinskaitė A, Rudėnaitė A, Jančorienė L, Ročka S, Verkhratsky A, Pivoriūnas A. bioRxiv; 2023.
Antigens from the Helminth Fasciola hepatica Exert Antiviral Effects against SARS-CoV-2 In Vitro.
Serrat J, Francés-Gómez C, Becerro-Recio D, González-Miguel J, [...], Siles-Lucas M.
Int J Mol Sci. 2023; 24 (14)
DOI: 10.3390/ijms241411597
SARS-CoV-2, the causal agent of COVID-19, is a new coronavirus that has rapidly spread worldwide and significantly impacted human health by causing a severe acute respiratory syndrome boosted by a pulmonary hyperinflammatory response. Previous data from our lab showed that the newly excysted juveniles of the helminth parasite Fasciola hepatica (FhNEJ) modulate molecular routes within host cells related to vesicle-mediated transport and components of the innate immune response, which could potentially be relevant during viral infections. Therefore, the aim of the present study was to determine whether FhNEJ-derived molecules influence SARS-CoV-2 infection efficiency in Vero cells. Pre-treatment of Vero cells with a tegument-enriched antigenic extract of FhNEJ (FhNEJ-TEG) significantly reduced infection by both vesicular stomatitis virus particles pseudotyped with the SARS-CoV-2 Spike protein (VSV-S2) and live SARS-CoV-2. Pre-treatment of the virus itself with FhNEJ-TEG prior to infection also resulted in reduced infection efficiency similar to that obtained by remdesivir pre-treatment. Remarkably, treatment of Vero cells with FhNEJ-TEG after VSV-S2 entry also resulted in reduced infection efficiency, suggesting that FhNEJ-TEG may also affect post-entry steps of the VSV replication cycle. Altogether, our results could potentially encourage the production of FhNEJ-derived molecules in a safe, synthetic format for their application as therapeutic agents against SARS-CoV-2 and other related respiratory viruses.
2023-07-18 2023 other research-article; Journal Article abstract-available 10.3390/ijms241411597 Antigens from the Helminth <i>Fasciola hepatica</i> Exert Antiviral Effects against SARS-CoV-2 In Vitro. Serrat J, Francés-Gómez C, Becerro-Recio D, González-Miguel J, Geller R, Siles-Lucas M. Int J Mol Sci. 2023; 24 (14)
Self-Amplifying RNA: A Second Revolution of mRNA Vaccines against COVID-19.
Silva-Pilipich N, Beloki U, Salaberry L, Smerdou C.
Vaccines (Basel). 2024; 12 (3)
DOI: 10.3390/vaccines12030318
SARS-CoV-2 virus, the causative agent of COVID-19, has produced the largest pandemic in the 21st century, becoming a very serious health problem worldwide. To prevent COVID-19 disease and infection, a large number of vaccines have been developed and approved in record time, including new vaccines based on mRNA encapsulated in lipid nanoparticles. While mRNA-based vaccines have proven to be safe and effective, they are more expensive to produce compared to conventional vaccines. A special type of mRNA vaccine is based on self-amplifying RNA (saRNA) derived from the genome of RNA viruses, mainly alphaviruses. These saRNAs encode a viral replicase in addition to the antigen, usually the SARS-CoV-2 spike protein. The replicase can amplify the saRNA in transfected cells, potentially reducing the amount of RNA needed for vaccination and promoting interferon I responses that can enhance adaptive immunity. Preclinical studies with saRNA-based COVID-19 vaccines in diverse animal models have demonstrated the induction of robust protective immune responses, similar to conventional mRNA but at lower doses. Initial clinical trials have confirmed the safety and immunogenicity of saRNA-based vaccines in individuals that had previously received authorized COVID-19 vaccines. These findings have led to the recent approval of two of these vaccines by the national drug agencies of India and Japan, underscoring the promising potential of this technology.
2024-03-17 2024 other review-article; Review; Journal Article abstract-available 10.3390/vaccines12030318 Self-Amplifying RNA: A Second Revolution of mRNA Vaccines against COVID-19. Silva-Pilipich N, Beloki U, Salaberry L, Smerdou C. Vaccines (Basel). 2024; 12 (3)
MICaFVi: A Novel Magnetic Immuno-Capture Flow Virometry Nano-Based Diagnostic Tool for Detection of Coronaviruses.
Samman N, El-Boubbou K, Al-Muhalhil K, Ali R, [...], Nehdi A.
Biosensors (Basel). 2023; 13 (5)
DOI: 10.3390/bios13050553
COVID-19 has resulted in a pandemic that aggravated the world's healthcare systems, economies, and education, and caused millions of global deaths. Until now, there has been no specific, reliable, and effective treatment to combat the virus and its variants. The current standard tedious PCR-based tests have limitations in terms of sensitivity, specificity, turnaround time, and false negative results. Thus, an alternative, rapid, accurate, and sensitive diagnostic tool that can detect viral particles, without the need for amplification or viral replication, is central to infectious disease surveillance. Here, we report MICaFVi (Magnetic Immuno-Capture Flow Virometry), a novel precise nano-biosensor diagnostic assay for coronavirus detection which combines the MNP-based immuno-capture of viruses for enrichment followed by flow-virometry analysis, enabling the sensitive detection of viral particles and pseudoviruses. As proof of concept, virus-mimicking spike-protein-coated silica particles (VM-SPs) were captured using anti-spike-antibody-conjugated MNPs (AS-MNPs) followed by detection using flow cytometry. Our results showed that MICaFVi can successfully detect viral MERS-CoV/SARS-CoV-2-mimicking particles as well as MERS-CoV pseudoviral particles (MERSpp) with high specificity and sensitivity, where a limit of detection (LOD) of 3.9 µg/mL (20 pmol/mL) was achieved. The proposed method has great potential for designing practical, specific, and point-of-care testing for rapid and sensitive diagnoses of coronavirus and other infectious diseases.
2023-05-18 2023 other research-article; Journal Article abstract-available 10.3390/bios13050553 MICaFVi: A Novel Magnetic Immuno-Capture Flow Virometry Nano-Based Diagnostic Tool for Detection of Coronaviruses. Samman N, El-Boubbou K, Al-Muhalhil K, Ali R, Alaskar A, Alharbi NK, Nehdi A. Biosensors (Basel). 2023; 13 (5)
Impact of nanotechnology on conventional and artificial intelligence-based biosensing strategies for the detection of viruses.
Ramalingam M, Jaisankar A, Cheng L, Krishnan S, [...], Marrazza G.
Discov Nano. 2023; 18 (1)
DOI: 10.1186/s11671-023-03842-4
Recent years have witnessed the emergence of several viruses and other pathogens. Some of these infectious diseases have spread globally, resulting in pandemics. Although biosensors of various types have been utilized for virus detection, their limited sensitivity remains an issue. Therefore, the development of better diagnostic tools that facilitate the more efficient detection of viruses and other pathogens has become important. Nanotechnology has been recognized as a powerful tool for the detection of viruses, and it is expected to change the landscape of virus detection and analysis. Recently, nanomaterials have gained enormous attention for their value in improving biosensor performance owing to their high surface-to-volume ratio and quantum size effects. This article reviews the impact of nanotechnology on the design, development, and performance of sensors for the detection of viruses. Special attention has been paid to nanoscale materials, various types of nanobiosensors, the internet of medical things, and artificial intelligence-based viral diagnostic techniques.
2023-04-01 2023 other review-article; Review; Journal Article abstract-available 10.1186/s11671-023-03842-4 Impact of nanotechnology on conventional and artificial intelligence-based biosensing strategies for the detection of viruses. Ramalingam M, Jaisankar A, Cheng L, Krishnan S, Lan L, Hassan A, Sasmazel HT, Kaji H, Deigner HP, Pedraz JL, Kim HW, Shi Z, Marrazza G. Discov Nano. 2023; 18 (1)
Photodynamic Inactivation of Bovine Coronavirus with the Photosensitizer Toluidine Blue O.
Zaharieva MM, Foka P, Karamichali E, Kroumov AD, [...], Najdenski HM.
Viruses. 2023; 16 (1)
DOI: 10.3390/v16010048
Coronaviruses (CoVs) belong to the group of enveloped positive-sense single-strand RNA viruses and are causative agents of respiratory, gastro-intestinal, and central nervous systems diseases in many host species, i.e., birds, mammals, and humans. Beta-CoVs revealed a great potential to cross the barrier between species by causing three epidemics/pandemics among humans in the 21st century. Considering the urgent need for powerful antiviral agents for decontamination, prevention, and treatment of BCoV infections, we turned our attention to the possibility of photodynamic inactivation with photosensitizers in combination with light irradiation. In the present study, we evaluated, for the first time, the antiviral activity of toluidine blue O (TBO) against Beta-coronavirus 1 (BCoV) in comparison to methylene blue (MB). First, we determined the in vitro cytotoxicity of MB and TBO on the Madin-Darby bovine kidney (MDBK) cell line with ISO10993-5/Annex C. Thereafter, BCoV was propagated in MDBK cells, and the virus titer was measured with digital droplet PCR, TCID50 assay and plaque assay. The antiviral activity of non-toxic concentrations of TBO was estimated using the direct inactivation approach. All effects were calculated in MAPLE 15® mathematical software by developing programs for non-linear modeling and response surface analysis. The median inhibitory concentration (IC50) of TBO after 72 h of incubation in MDBK cells was 0.85 µM. The antiviral activity of TBO after the direct inactivation of BCoV (MOI = 1) was significantly stronger than that of MB. The median effective concentration (EC50) of TBO was 0.005 µM. The cytopathic effect decreased in a concentration-dependent manner, from 0.0025 to 0.01 µM, and disappeared fully at concentrations between 0.02 and 0.3 µM of TBO. The number of virus particles also decreased, depending on the concentration applied, as proven by ddPCR analysis. In conclusion, TBO exhibits significant potential for direct inactivation of BCoV in vitro, with a very high selectivity index, and should be subjected to further investigation, aiming at its application in veterinary and/or human medical practice.
2023-12-27 2023 other research-article; Journal Article abstract-available 10.3390/v16010048 Photodynamic Inactivation of Bovine Coronavirus with the Photosensitizer Toluidine Blue O. Zaharieva MM, Foka P, Karamichali E, Kroumov AD, Philipov S, Ilieva Y, Kim TC, Podlesniy P, Manasiev Y, Kussovski V, Georgopoulou U, Najdenski HM. Viruses. 2023; 16 (1)
DNA electroporation in a vacuum: A "shocking" innovation for vaccines.
Silva-Pilipich N, Lasarte-Cía A, Lasarte JJ, Smerdou C.
Mol Ther Nucleic Acids. 2024; 35 (1)
DOI: 10.1016/j.omtn.2023.102110
2024-01-05 2024 other News 10.1016/j.omtn.2023.102110 DNA electroporation in a vacuum: A "shocking" innovation for vaccines. Silva-Pilipich N, Lasarte-Cía A, Lasarte JJ, Smerdou C. Mol Ther Nucleic Acids. 2024; 35 (1)
Immunisation efficacy of a stabilised SARS-CoV-2 spike glycoprotein in two geriatric animal models.
Usai C, Ainsua-Enrich E, Gales VU, Pradenas E, [...], Segalés J.
NPJ Vaccines. 2024; 9 (1)
DOI: 10.1038/s41541-024-00840-0
Age is associated with reduced efficacy of vaccines and linked to higher risk of severe COVID-19. Here we determined the impact of ageing on the efficacy of a SARS-CoV-2 vaccine based on a stabilised Spike glycoprotein (S-29) that had previously shown high efficacy in young animals. Thirteen to 18-month-old golden Syrian hamsters (GSH) and 22-23-month-old K18-hCAE2 mice were immunised twice with S-29 protein in AddaVaxTM adjuvant. GSH were intranasally inoculated with SARS-CoV-2 either two weeks or four months after the booster dose, while all K18-hACE2 mice were intranasally inoculated two weeks after the second immunisation. Body weight and clinical signs were recorded daily post-inoculation. Lesions and viral load were investigated in different target tissues. Immunisation induced seroconversion and production of neutralising antibodies; however, animals were only partially protected from weight loss. We observed a significant reduction in the amount of viral RNA and a faster viral protein clearance in the tissues of immunized animals. Infectious particles showed a faster decay in vaccinated animals while tissue lesion development was not altered. In GSH, the shortest interval between immunisation and inoculation reduced RNA levels in the lungs, while the longest interval was equally effective in reducing RNA in nasal turbinates; viral nucleoprotein amount decreased in both tissues. In mice, immunisation was able to improve the survival of infected animals. Despite the high protection shown in young animals, S-29 efficacy was reduced in the geriatric population. Our research highlights the importance of testing vaccine efficacy in older animals as part of preclinical vaccine evaluation.
2024-02-27 2024 other research-article; Journal Article abstract-available 10.1038/s41541-024-00840-0 Immunisation efficacy of a stabilised SARS-CoV-2 spike glycoprotein in two geriatric animal models. Usai C, Ainsua-Enrich E, Gales VU, Pradenas E, Lorca-Oró C, Tarrés-Freixas F, Roca N, Pérez M, Ávila-Nieto C, Rodríguez de la Concepción ML, Pedreño-Lopez N, Carabelli J, Trinité B, Ballana E, Riveira-Muñoz E, Izquierdo-Useros N, Clotet B, Blanco J, Guallar V, Cantero G, Vergara-Alert J, Carrillo J, Segalés J. NPJ Vaccines. 2024; 9 (1)
Could Pulmonary Inflammation of COVID-19 ARDS Patients Worsen Due to an Excessive Repetition of Follow up Radiological Studies?
Macias-Verde D, Burgos-Burgos J, Lara PC, Calabrese E.
Preprints.org; 2023.
DOI: 10.20944/preprints202305.0829.v1
United Nations Scientific Committee on the Effects of 2006 report was the first document released by an abandoned the classical paradigm that ionizing suppressive, considering the idea that at low doses enhances the appearance of antiinflammatory biomarkers [UNSCEAR 2006]. It considers energetic an immune modulation agent due to the multitude the innate immune system, depending on various age, health status, co-morbidities, genetic background, co-stressors [Lumniczky et al.]. Natural background radiation is the most hazardous public health, followed by medical imaging as a close Naturally occurring radionuclides attach to particulate ionizing radiation after inhalation and deposition in the in this article that exposure to particle radioactivity of inflammation. With that purpose, we have done an on common anti-inflammatory biomarkers between cases on COVID-19 elderly patients, and those found low-intensity natural ionizing radiation in locations with hypothesize that radioactivity increases biomarkers of strategy involved the use of databases from PubMed, (e.g., dose response, hormesis, J-shaped, NLRP3 LNT model, etc.). Extrapolating these effects to artificial ionizing radiation drawn conclusions on the over use of X-ray computed images in elderly ICU admitted patients with pulmonary oxygen species (ROS) generation by this action seems inflammation of leucine-rich protein 3 (NLRP3) inflammasome, waking up an over cytokine production.
2023-05-11 2023 other Preprint abstract-available 10.20944/preprints202305.0829.v1 Could Pulmonary Inflammation of COVID-19 ARDS Patients Worsen Due to an Excessive Repetition of Follow up Radiological Studies? Macias-Verde D, Burgos-Burgos J, Lara PC, Calabrese E. Preprints.org; 2023.
Potent Neutralizing Activity of Polyclonal Equine Antibodies Against Severe Acute Respiratory Syndrome Coronavirus 2 Variants of Concern.
Luczkowiak J, Radreau P, Nguyen L, Labiod N, [...], Delgado R.
J Infect Dis. 2022; 227 (1)
DOI: 10.1093/infdis/jiac331
Several anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) monoclonal antibodies (mAbs) have received emergency authorization for coronavirus disease 2019 (COVID-19) treatment. However, most of these mAbs are not active against the highly mutated Omicron SARS-CoV-2 subvariants. We have tested a polyclonal approach of equine anti-SARS-CoV-2 F(ab')2 antibodies that achieved a high level of neutralizing potency against all SARS-CoV-2 variants of concern tested including Omicron BA.1, BA.2, BA.2.12 and BA.4/5. A repertoire of antibodies targeting conserved epitopes in different regions of the spike protein could plausibly account for this remarkable breadth of neutralization. These results warrant the clinical investigation of equine polyclonal F(ab')2 antibodies as a novel therapeutic strategy against COVID-19.
2022-12-01 2022 other brief-report; Research Support, Non-U.S. Gov't; Journal Article abstract-available 10.1093/infdis/jiac331 Potent Neutralizing Activity of Polyclonal Equine Antibodies Against Severe Acute Respiratory Syndrome Coronavirus 2 Variants of Concern. Luczkowiak J, Radreau P, Nguyen L, Labiod N, Lasala F, Veas F, Herbreteau CH, Delgado R. J Infect Dis. 2022; 227 (1)
Puzzles, challenges, and information reservoir of SARS-CoV-2 quasispecies.
Domingo E, Martínez-González B, García-Crespo C, Somovilla P, [...], Perales C.
J Virol. 2023; 97 (12)
DOI: 10.1128/jvi.01511-23
Upon the emergence of SARS-CoV-2 in the human population, it was conjectured that for this coronavirus the dynamic intra-host heterogeneity typical of RNA viruses would be toned down. Nothing of this sort is observed. Here we review the main observations on the complexity and diverse composition of SARS-CoV-2 mutant spectra sampled from infected patients, within the framework of quasispecies dynamics. The analyses suggest that the information provided by myriads of genomic sequences within infected individuals may have a predictive value of the genomic sequences that acquire epidemiological relevance. Possibilities to reconcile the presence of broad mutant spectra in the large RNA coronavirus genome with its encoding a 3' to 5' exonuclease proofreading-repair activity are considered. Indeterminations in the behavior of individual viral genomes provide a benefit for the survival of the ensemble. We propose that this concept falls in the domain of "stochastic thinking," a notion that applies also to cellular processes, as a means for biological systems to face unexpected needs.
2023-11-21 2023 other review-article; Review; Journal Article abstract-available 10.1128/jvi.01511-23 Puzzles, challenges, and information reservoir of SARS-CoV-2 quasispecies. Domingo E, Martínez-González B, García-Crespo C, Somovilla P, de Ávila AI, Soria ME, Durán-Pastor A, Perales C. J Virol. 2023; 97 (12)
Predictive Factors and ACE-2 Gene Polymorphisms in Susceptibility to Long COVID-19 Syndrome.
Varillas-Delgado D, Jimenez-Antona C, Lizcano-Alvarez A, Cano-de-la-Cuerda R, [...], Laguarta-Val S.
Int J Mol Sci. 2023; 24 (23)
DOI: 10.3390/ijms242316717
Long COVID-19 syndrome is present in 5-10% of patients infected with SARS-CoV-2, and there is still little information on the predisposing factors that lead to its development. The purpose of the study was to evaluate the predictive factors in early symptoms, clinical features and the role of Angiotensin-Converting Enzyme-2 (ACE-2) c.513-1451G>A (rs2106806) and c.15643279T>C (rs6629110) polymorphisms in the susceptibility to developing Long COVID-19 syndrome subsequent to COVID-19 infectionA total of 29 patients who suffered COVID-19 were recruited in a descriptive longitudinal study of two groups: Long COVID-19 (n = 16) and non-Long COVID-19 (n = 13). Early symptoms and clinical features during COVID-19 were classified by a medical service. ACE-2 polymorphisms were genotyped by using a Single Nucleotide Primer Extension (SNPE). Of the early symptoms, fatigue, myalgia and headache showed a high risk of increasing Long COVID-19 susceptibility. Clinical features such as emergency care, SARS-CoV-2 reinfection, previous diseases, respiratory disease and brain fog also had a high risk of increasing Long COVID-19 susceptibility. The A allele in the rs2106806 variant was associated with an odds ratio (OR) of 4.214 (95% CI 2.521-8.853; p < 0.001), and the T allele in the rs6629110 variant was associated with an OR of 3.754 (95% CI 1.785-6.105; p = 0.002) of increasing Long COVID-19 susceptibility. This study shows the risk of ACE-2 polymorphisms, different early symptoms and clinical features during SARS-CoV-2 infection in susceptibility to Long COVID-19.
2023-11-24 2023 other research-article; Journal Article abstract-available 10.3390/ijms242316717 Predictive Factors and <i>ACE-2</i> Gene Polymorphisms in Susceptibility to Long COVID-19 Syndrome. Varillas-Delgado D, Jimenez-Antona C, Lizcano-Alvarez A, Cano-de-la-Cuerda R, Molero-Sanchez A, Laguarta-Val S. Int J Mol Sci. 2023; 24 (23)
Novel Spike-stabilized trimers with improved production protect K18-hACE2 mice and golden Syrian hamsters from the highly pathogenic SARS-CoV-2 Beta variant
Ávila-Nieto C, Vergara-Alert J, Amengual-Rigo P, Ainsua-Enrich E, [...], Carrillo J.
bioRxiv; 2023.
DOI: 10.1101/2023.07.07.548077
Most COVID-19 vaccines are based on the SARS-CoV-2 Spike glycoprotein (S) or their subunits. However, the S shows some structural instability that limits its immunogenicity and production, hampering the development of recombinant S-based vaccines. The introduction of the K986P and V987P (S-2P) mutations increases the production of the recombinant S trimer and, more importantly, its immunogenicity, suggesting that these two parameters are related. However, S-2P still shows some molecular instability and it is produced with low yield. Thus, S-2P production can be further optimized. Here we described a novel set of mutations identified by molecular modelling and located in the S2 region of the Spike that increase S-2P production up to five-fold. Besides their immunogenicity, the efficacy of two representative S-2P-based mutants, S-29 and S-21, protecting from a heterologous SARS-CoV-2 Beta variant challenge was assayed in K18-hACE2 mice (an animal model of severe SARS-CoV-2 disease) and golden Syrian hamsters (GSH) (a moderate disease model). S-21 induced higher level of WH1 and Delta variants neutralizing antibodies than S-2P in K18-hACE2 mice three days after challenge. Viral load in nasal turbinate and oropharyngeal samples were reduced in S-21 and S-29 vaccinated mice. Despite that, only the S-29 protein protected 100% of K18-hACE2 mice from severe disease. When GSH were analyzed, all immunized animals were protected from disease development irrespectively of the immunogen they received. Therefore, the higher yield of S-29, as well as its improved immunogenicity and efficacy protecting from the highly pathogenic SARS-CoV-2 Beta variant, pinpoint the S-29 spike mutant as an alternative to the S-2P protein for future SARS-CoV-2 vaccine development.

Authors summary

The rapid development of SARS-CoV-2 vaccines have been pivotal in the control of the COVID-19 pandemic worldwide. Most of these vaccines include the S glycoprotein as the main immunogen since this protein, and particularly its receptor binding domain (RBD), is the major target of neutralizing antibodies. SARS-CoV-2 have been evolving from the beginning of the pandemic and several variants with increased transmissibility, pathogenicity or resistance to infection– or vaccine-induced immunity have emerged. Different strategies have been adopted to improve vaccine protection including additional booster doses or the adaptation of the S immunogens to the novel SARS-CoV-2 variants. As a complementary strategy we have identified a combination of non-proline mutations that increase S production by 5-fold (S-29 protein). Despite the sequence of this novel S-29 immunogen is based on the ancestral SARS-CoV-2 WH1 variant, it effectively protects animal model from the highly pathogenic and neutralization resistant SARS-CoV-2 Beta variant. Thus, we describe a novel set of mutations that can increase the production and efficacy of S-based COVID-19 vaccines.
2023-07-07 2023 other Preprint abstract-available 10.1101/2023.07.07.548077 Novel Spike-stabilized trimers with improved production protect K18-hACE2 mice and golden Syrian hamsters from the highly pathogenic SARS-CoV-2 Beta variant Ávila-Nieto C, Vergara-Alert J, Amengual-Rigo P, Ainsua-Enrich E, Brustolin M, de la Concepción MLR, Pedreño-Lopez N, Rodon J, Urrea V, Pradenas E, Marfil S, Ballana E, Riveira-Muñoz E, Pérez M, Roca N, Tarrés-Freixas F, Carabelli J, Cantero G, Pons-Grífols A, Rovirosa C, Aguilar-Gurrieri C, Ortiz R, Barajas A, Trinité B, Lepore R, Muñoz-Basagoiti J, Perez-Zsolt D, Izquierdo-Useros N, Valencia A, Blanco J, Clotet B, Guallar V, Segalés J, Carrillo J. bioRxiv; 2023.
Detection of SARS-CoV-2 in a dog with hemorrhagic diarrhea.
Padilla-Blanco M, Vega S, Enjuanes L, Morey A, [...], Rubio-Guerri C.
BMC Vet Res. 2022; 18 (1)
DOI: 10.1186/s12917-022-03453-8

Background

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, has infected several animal species, including dogs, presumably via human-to-animal transmission. Most infected dogs reported were asymptomatic, with low viral loads. However, in this case we detected SARS-CoV-2 in a dog from the North African coastal Spanish city of Ceuta presenting hemorrhagic diarrhea, a disease also reported earlier on in an infected dog from the USA.

Case presentation

In early January 2021, a West Highland Terrier pet dog from Ceuta (Spain) presented hemorrhagic diarrhea with negative tests for candidate microbial pathogens. Since the animal was in a household whose members suffered SARS-CoV-2 in December 2020, dog feces were analyzed for SARS-CoV-2, proving positive in a two-tube RT-PCR test, with confirmation by sequencing a 399-nucleotide region of the spike (S) gene. Furthermore, next-generation sequencing (NGS) covered > 90% SARS-CoV-2 genome sequence, allowing to classify it as variant B.1.177. Remarkably, the sequence revealed the Ile402Val substitution in the spike protein (S), of potential concern because it mapped in the receptor binding domain (RBD) that mediates virus interaction with the cell. NGS reads mapping to bacterial genomes showed that the dog fecal microbiome fitted best the characteristic microbiome of dog's acute hemorrhagic diarrhea.

Conclusion

Our findings exemplify dog infection stemming from the human SARS-CoV-2 pandemic, providing nearly complete-genome sequencing of the virus, which is recognized as belonging to the B.1.177 variant, adding knowledge on variant circulation in a geographic region and period for which there was little viral variant characterization. A single amino acid substitution found in the S protein that could have been of concern is excluded to belong to this category given its rarity and intrinsic nature. The dog's pathology suggests that SARS-CoV-2 could affect the gastrointestinal tract of the dog.
2022-10-12 2022 other Journal Article; Case Reports; case-report abstract-available 10.1186/s12917-022-03453-8 Detection of SARS-CoV-2 in a dog with hemorrhagic diarrhea. Padilla-Blanco M, Vega S, Enjuanes L, Morey A, Lorenzo T, Marín C, Ivorra C, Maiques E, Rubio V, Rubio-Guerri C. BMC Vet Res. 2022; 18 (1)
SARS‑CoV‑2 and Seizure: An Insight Into the Pathophysiology.
Ahadiat SAA, Hosseinian Z.
Anesth Pain Med. 2023; 13 (1)
DOI: 10.5812/aapm-134129
2023-01-16 2023 other letter; Journal Article 10.5812/aapm-134129 SARS‑CoV‑2 and Seizure: An Insight Into the Pathophysiology. Ahadiat SAA, Hosseinian Z. Anesth Pain Med. 2023; 13 (1)
Highly Attenuated Poxvirus-Based Vaccines Against Emerging Viral Diseases.
Perdiguero B, Pérez P, Marcos-Villar L, Albericio G, [...], Esteban M.
J Mol Biol. 2023; 435 (15)
DOI: 10.1016/j.jmb.2023.168173
Although one member of the poxvirus family, variola virus, has caused one of the most devastating human infections worldwide, smallpox, the knowledge gained over the last 30 years on the molecular, virological and immunological mechanisms of these viruses has allowed the use of members of this family as vectors for the generation of recombinant vaccines against numerous pathogens. In this review, we cover different aspects of the history and biology of poxviruses with emphasis on their application as vaccines, from first- to fourth-generation, against smallpox, monkeypox, emerging viral diseases highlighted by the World Health Organization (COVID-19, Crimean-Congo haemorrhagic fever, Ebola and Marburg virus diseases, Lassa fever, Middle East respiratory syndrome and severe acute respiratory syndrome, Nipah and other henipaviral diseases, Rift Valley fever and Zika), as well as against one of the most concerning prevalent virus, the Human Immunodeficiency Virus, the causative agent of Acquired Immunodeficiency Syndrome. We discuss the implications in human health of the 2022 monkeypox epidemic affecting many countries, and the rapid prophylactic and therapeutic measures adopted to control virus dissemination within the human population. We also describe the preclinical and clinical evaluation of the Modified Vaccinia virus Ankara and New York vaccinia virus poxviral strains expressing heterologous antigens from the viral diseases listed above. Finally, we report different approaches to improve the immunogenicity and efficacy of poxvirus-based vaccine candidates, such as deletion of immunomodulatory genes, insertion of host-range genes and enhanced transcription of foreign genes through modified viral promoters. Some future prospects are also highlighted.
2023-06-08 2023 other Research Support, Non-U.S. Gov't; review-article; Review; Journal Article abstract-available 10.1016/j.jmb.2023.168173 Highly Attenuated Poxvirus-Based Vaccines Against Emerging Viral Diseases. Perdiguero B, Pérez P, Marcos-Villar L, Albericio G, Astorgano D, Álvarez E, Sin L, Gómez CE, García-Arriaza J, Esteban M. J Mol Biol. 2023; 435 (15)
SARS-CoV-2 Infection and Preeclampsia-How an Infection Can Help Us to Know More about an Obstetric Condition.
González-Vanegas O, Martinez-Perez O.
Viruses. 2023; 15 (7)
DOI: 10.3390/v15071564
Pregnant women with SARS-CoV-2 infection have a significantly higher risk of maternal death, ICU admission, preterm delivery, and stillbirth compared to those without infection. Additionally, the risk of preeclampsia (PE) increases in pregnant women infected with SARS-CoV-2, particularly in severe cases. The association between COVID-19 and PE is likely attributed to various mechanisms, including direct effects of the virus on trophoblast function and the arterial wall, exaggerated inflammatory response in pregnant women, local inflammation leading to placental ischemia, SARS-CoV-2-related myocardial injury, cytokine storm, and thrombotic microangiopathy. This paper aims to explore the similarities between PE and SARS-CoV-2 infection, considering COVID-19 as a valuable study model. By examining these parallels, we can enhance our knowledge and comprehension of PE. We wish to emphasize the potential for COVID-19-induced myocardial injury in pregnant women and its connection to the increased maternal mortality rate.
2023-07-17 2023 other Research Support, Non-U.S. Gov't; review-article; Review; Journal Article abstract-available 10.3390/v15071564 SARS-CoV-2 Infection and Preeclampsia-How an Infection Can Help Us to Know More about an Obstetric Condition. González-Vanegas O, Martinez-Perez O. Viruses. 2023; 15 (7)
Clinical experience in the treatment of COVID-19 with monoclonal antibodies in solid organ transplant recipients.
Múñez-Rubio E, Calderón-Parra J, Gutiérrez-Villanueva A, Fernández-Cruz A, [...], Ramos-Martínez A.
Rev Esp Quimioter. 2023; 36 Suppl 1
DOI: 10.37201/req/s01.07.2023
Solid organ transplant (SOT) recipients are at high risk for complications from coronavirus disease 2019 (COVID-19). SOT recipients mount lower immunological responses to vaccines than general population and are at high risk for breakthrough COVID-19 infections. Passive immunotherapy in the form of anti-Spike monoclonal antibodies (MoAbs) may be an alternative for the prophylaxis and treatment of COVID-19 in these patients. SARS-CoV-2 has evolved by accumulating resistance mutations that have escaped the neutralizing action of most MoAbs. However, MoAbs directed at more conserved epitopes and that maintain effector functions could maintain efficacy in the treatment of these patients. According to published data, SOT recipients with low anti-spike antibody responses to vaccination could benefit from the use of MoAbs in pre-exposure prophylaxis, in the treatment of COVID-19 mild to moderate and severe COVID-19 with less than 15 days of symptom duration and low oxygen requirements. Combination therapy could be more effective than monotherapy for the treatment of mild-to-moderate SARS-CoV-2 infection.
2023-11-24 2023 other research-article; Review; Journal Article abstract-available 10.37201/req/s01.07.2023 Clinical experience in the treatment of COVID-19 with monoclonal antibodies in solid organ transplant recipients. Múñez-Rubio E, Calderón-Parra J, Gutiérrez-Villanueva A, Fernández-Cruz A, Ramos-Martínez A. Rev Esp Quimioter. 2023; 36 Suppl 1
CompCorona: A Web Portal for Comparative Analysis of the Host Transcriptome of PBMC and Lung SARS-CoV-2, SARS-CoV, and MERS-CoV
Salihoğlu R, Saraçoğlu F, Sibai M, Zengin T, [...], Önal-Süzek T.
bioRxiv; 2023.
DOI: 10.1101/2023.01.21.524927

Motivation

Understanding the host response to SARS-CoV-2 infection is crucial for deciding on the correct treatment of this epidemic disease. Although several recent studies reported the comparative transcriptome analyses of the three coronaviridae (CoV) members; namely SARS-CoV, MERS-CoV, and SARS-CoV-2, there is yet to exist a web-tool to compare increasing number of host transcriptome response datasets against the pre-processed CoV member datasets. Therefore, we developed a web application called CompCorona, which allows users to compare their own transcriptome data of infected host cells with our pre-built datasets of the three epidemic CoVs, as well as perform functional enrichment and principal component analyses (PCA).

Results

Comparative analyses of the transcriptome profiles of the three CoVs revealed that numerous differentially regulated genes directly or indirectly related to several diseases (e.g., hypertension, male fertility, ALS, and epithelial dysfunction) are altered in response to CoV infections. Transcriptome similarities and differences between the host PBMC and lung tissue infected by SARS-CoV-2 are presented. Most of our findings are congruent with the clinical cases recorded in the literature. Hence, we anticipate that our results will significantly contribute to ongoing studies investigating the pre-and/or post-implications of SARS-CoV-2 infection. In addition, we implemented a user-friendly public website, CompCorona for biomedical researchers to compare users own CoV-infected host transcriptome data against the built-in CoV datasets and visualize their results via interactive PCA, UpSet and Pathway plots.

Availability

CompCorona is freely available on the web at http://compcorona.mu.edu.tr

Contact

tugbasuzek@mu.edu.tr
2023-01-23 2023 other Preprint abstract-available 10.1101/2023.01.21.524927 CompCorona: A Web Portal for Comparative Analysis of the Host Transcriptome of PBMC and Lung SARS-CoV-2, SARS-CoV, and MERS-CoV Salihoğlu R, Saraçoğlu F, Sibai M, Zengin T, Masud BA, Karasoy O, Önal-Süzek T. bioRxiv; 2023.
Proteomic snapshot of saliva samples predicts new pathways implicated in SARS-CoV-2 pathogenesis
Olmo EMd, Ciordia S, Santos FM, Jiménez D, [...], Serrano-Villar S.
Authorea Preprints; 2023.
DOI: 10.22541/au.169348865.59420347/v1
The information on the microbiome’s human pathways and active members that can affect SARS-CoV-2 susceptibility and pathogenesis in the salivary proteome is very scarce. Here, we studied samples collected from April to June 2020 from unvaccinated patients. We compared 10 infected and hospitalized patients with severe (n=5) and moderate (n=5) Coronavirus Disease (COVID-19) with 10 uninfected individuals, including Non-COVID but susceptible individuals (n=5) and Non-COVID and non-susceptible healthcare workers with repeated high-risk exposures (n=5). By performing high-throughput proteomic profiling in saliva samples, we detected 226 unique differentially expressed (DE) human proteins between groups (q-value ≤0.05) out of 2721 unambiguously identified proteins (false discovery rate ≤1%). Major differences were observed between the Non-COVID vs the non-susceptible groups. Bioinformatics analysis of DE proteins revealed human proteomic signatures related to inflammatory responses, central cellular processes, and antiviral activity associated with saliva of SARS-CoV-2 infected patients (p-value ≤0.0004). Discriminatory biomarker signatures from human saliva include cystatins, protective molecules present in the oral cavity, calprotectins, involved in cell cycle progression, and histones, related to nucleosome functions. The expression level of two human proteins related to protein transport in the cytoplasm, named DYNC1 (p-value, 0.0021) and MAPRE1 (p-value, 0.047), correlated with angiotensin-converting enzyme 2 (ACE2) plasma activity. Finally, the proteomes of microorganisms present in the saliva samples showed 4 main microbial functional features related to ribosome functioning that are overrepresented in the infected group. Our study explores potential candidates involved in pathways implicated in SARS-CoV-2 susceptibility although further studies in larger cohorts will be necessary.
2023-08-31 2023 other Preprint abstract-available 10.22541/au.169348865.59420347/v1 Proteomic snapshot of saliva samples predicts new pathways implicated in SARS-CoV-2 pathogenesis Olmo EMd, Ciordia S, Santos FM, Jiménez D, Martínez-Sanz J, Vizcarra P, Ron R, Sánchez-Conde M, Bargiela R, Sanchez-Carrillo S, Moreno S, Corrales FJ, Ferrer M, Serrano-Villar S. Authorea Preprints; 2023.
Liposomal Lactoferrin Exerts Antiviral Activity against HCoV-229E and SARS-CoV-2 Pseudoviruses In Vitro.
Andreu S, Ripa I, Bello-Morales R, López-Guerrero JA.
Viruses. 2023; 15 (4)
DOI: 10.3390/v15040972
A limited number of effective therapies are currently available to treat human coronavirus SARS-CoV-2 and other human coronaviruses, which are responsible for nearly a third of global cases of the common cold. The possibility of new emerging coronaviruses demands powerful new antiviral strategies. Lactoferrin is a well-known protein that possesses anti-inflammatory and immunomodulatory activities, and it has previously shown antiviral activity against several viruses, including SARS-CoV-2. To increase this antiviral activity, here we present bovine liposomal lactoferrin. Liposomal encapsulation of the compound was proven to increase permeability, bioavailability, and time release. In the present work, we compare the antiviral activity of free and liposomal bovine lactoferrin against HCoV229E and SARS-CoV-2 in vitro and in human primary bronchial epithelial cells, and we demonstrated that the liposomal form exerts a more potent antiviral activity than its free form at non-cytotoxic doses.
2023-04-15 2023 other research-article; Journal Article abstract-available 10.3390/v15040972 Liposomal Lactoferrin Exerts Antiviral Activity against HCoV-229E and SARS-CoV-2 Pseudoviruses In Vitro. Andreu S, Ripa I, Bello-Morales R, López-Guerrero JA. Viruses. 2023; 15 (4)
Prevalence of Respiratory Viral Infections in Deceased Persons during the COVID-19 Pandemic Season 2021-2022: A Population-Based Observational Study.
Trobajo-Sanmartín C, Navascués A, Fernández-Huerta M, Martínez-Baz I, [...], Castilla J.
Viruses. 2024; 16 (4)
DOI: 10.3390/v16040533
Although the omicron variant of SARS-CoV-2 circulated intensely during the 2021-2022 season, many patients with severe acute respiratory disease tested negative for COVID-19. The aim of this study was to assess the presence of different respiratory viruses in deceased persons. The proportion of deceased persons with respiratory viral infections in the 2021-2022 season in Navarre, Spain, was estimated considering all deaths caused by confirmed COVID-19 according to the epidemiological surveillance and the results of multiplex PCR tests for respiratory viruses performed in a sample of deceased persons with a cause of death other than COVID-19. Of 3578 deaths, 324 (9.1%) were initially reported as caused by pre-mortem confirmed COVID-19. A sample of 242 persons who died by causes other than COVID-19 were tested post-mortem; 64 (26.4%) of them were positive for any respiratory virus: 11.2% for SARS-CoV-2, 5.8% for rhinovirus, 3.7% for human coronavirus, 2.5% for metapneumovirus, 1.7% for respiratory syncytial virus, 1.7% for parainfluenza, 1.2% for influenza, and less than 1% each for adenovirus and bocavirus. Combining both approaches, we estimated that 34.4% of all deceased persons during the study period had a respiratory viral infection and 19.2% had SARS-CoV-2. Only 33.3% (9/27) of SARS-CoV-2 and 5.0% (2/40) of other viruses detected post-mortem had previously been confirmed pre-mortem. In a period with very intense circulation of SARS-CoV-2 during the pandemic, other respiratory viruses were also frequently present in deceased persons. Some SARS-CoV-2 infections and most other viral infections were not diagnosed pre-mortem. Several respiratory viruses may contribute to excess mortality in winter.
2024-03-29 2024 other Research Support, Non-U.S. Gov't; research-article; Journal Article; Observational Study abstract-available 10.3390/v16040533 Prevalence of Respiratory Viral Infections in Deceased Persons during the COVID-19 Pandemic Season 2021-2022: A Population-Based Observational Study. Trobajo-Sanmartín C, Navascués A, Fernández-Huerta M, Martínez-Baz I, Casado I, Ezpeleta C, Castilla J. Viruses. 2024; 16 (4)
A monoclonal antibody targeting a large surface of the receptor binding motif shows pan-neutralizing SARS-CoV-2 activity.
de Campos-Mata L, Trinité B, Modrego A, Tejedor Vaquero S, [...], Magri G.
Nat Commun. 2024; 15 (1)
DOI: 10.1038/s41467-024-45171-9
Here we report the characterization of 17T2, a SARS-CoV-2 pan-neutralizing human monoclonal antibody isolated from a COVID-19 convalescent individual infected during the first pandemic wave. 17T2 is a class 1 VH1-58/κ3-20 antibody, derived from a receptor binding domain (RBD)-specific IgA+ memory B cell, with a broad neutralizing activity against former and new SARS-CoV-2 variants, including XBB.1.16 and BA.2.86 Omicron subvariants. Consistently, 17T2 demonstrates in vivo prophylactic and therapeutic activity against Omicron BA.1.1 infection in K18-hACE2 mice. Cryo-electron microscopy reconstruction shows that 17T2 binds the BA.1 spike with the RBD in "up" position and blocks the receptor binding motif, as other structurally similar antibodies do, including S2E12. Yet, unlike S2E12, 17T2 retains its neutralizing activity against all variants tested, probably due to a larger RBD contact area. These results highlight the impact of small structural antibody changes on neutralizing performance and identify 17T2 as a potential candidate for future clinical interventions.
2024-02-05 2024 other research-article; Journal Article abstract-available 10.1038/s41467-024-45171-9 A monoclonal antibody targeting a large surface of the receptor binding motif shows pan-neutralizing SARS-CoV-2 activity. de Campos-Mata L, Trinité B, Modrego A, Tejedor Vaquero S, Pradenas E, Pons-Grífols A, Rodrigo Melero N, Carlero D, Marfil S, Santiago C, Raïch-Regué D, Bueno-Carrasco MT, Tarrés-Freixas F, Abancó F, Urrea V, Izquierdo-Useros N, Riveira-Muñoz E, Ballana E, Pérez M, Vergara-Alert J, Segalés J, Carolis C, Arranz R, Blanco J, Magri G. Nat Commun. 2024; 15 (1)
Probable human origin of the SARS-CoV-2 polybasic furin cleavage motif.
Romeu AR.
BMC Genom Data. 2023; 24 (1)
DOI: 10.1186/s12863-023-01169-8

Background

The key evolutionary step leading to the pandemic virus was the acquisition of the PRRA furin cleavage motif at the spike glycoprotein S1/S2 junction by a progenitor of SARS-CoV-2. Two of its features draw attention: (i) it is absent in other known lineage B beta-coronaviruses, including the newly discovered coronaviruses in bats from Laos and Vietnam, which are the closest known relatives of the covid virus; and, (ii) it introduced the pair of arginine codons (CGG-CGG), whose usage is extremely rare in coronaviruses. With an occurrence rate of only 3%, the arginine CGG codon is considered a minority in SARS CoV-2. On the other hand, Laos and Vietnam bat coronaviruses contain receptor-binding domains that are almost identical to that of SARS-CoV-2 and can therefore infect human cells despite the absence of the furin cleavage motif.

Results

Based on these data, the aim of this work is to provide a detailed sequence analysis between the SARS-CoV-2 S gene insert encoding PRRA and the human mRNA transcripts. The result showed a 100% match to several mRNA transcripts. The set of human genes whose mRNAs match this S gene insert are ubiquitous and highly expressed, e.g., the ATPase F1 (ATP5F1) and the ubiquitin specific peptidase 21 (USP21) genes; or specific genes of target organs or tissues of the SARS-CoV-2 infection (e.g., MEMO1, SALL3, TRIM17, CWC15, CCDC187, FAM71E2, GAB4, PRDM13). Results suggest that a recombination between the genome of a SARS-CoV-2 progenitor and human mRNA transcripts could be the origin of the S gene 12-nucleotide insert encoding the S protein PRRA motif.

Conclusions

The hypothesis of probable human origin of the SARS-CoV-2 polybasic furin cleavage motif is supported by: (i) the nature of human genes whose mRNA sequence 100% match the S gene insert; (ii) the synonymous base substitution in the arginine codons (CGG-CGG); and (iii) further spike glycoprotein PRRA-like insertions suggesting that the acquisition of PRRA may not have been a single recombination event.
2023-11-21 2023 other research-article; Journal Article abstract-available 10.1186/s12863-023-01169-8 Probable human origin of the SARS-CoV-2 polybasic furin cleavage motif. Romeu AR. BMC Genom Data. 2023; 24 (1)
Targeting IL-6 trans-signalling by sgp130Fc attenuates severity in SARS-CoV-2 -infected mice and reduces endotheliopathy.
Rodríguez-Hernández MÁ, Baena-Bustos M, Carneros D, Zurita-Palomo C, [...], Bustos M.
EBioMedicine. 2024; 103
DOI: 10.1016/j.ebiom.2024.105132

Background

SARS-CoV-2 infection is considered as a relapsing inflammatory process with a dysregulation of IL-6 signalling. Classic IL-6 signalling is thought to represent a defence mechanism against pathogens. In contrast, IL-6 trans-signalling has pro-inflammatory effects. In severe COVID-19, therapeutic strategies have focused on global inhibition of IL-6, with controversial results. We hypothesized that specific blockade of IL-6 trans-signalling could inhibit inflammatory response preserving the host defence activity inherent to IL-6 classic signalling.

Methods

To test the role of the specific IL-6 trans-signalling inhibition by sgp130Fc in short- and long-term consequences of COVID-19, we used the established K18-hACE2 transgenic mouse model. Histological as well as immunohistochemical analysis, and pro-inflammatory marker profiling were performed. To investigate IL-6 trans-signalling in human cells we used primary lung microvascular endothelial cells and fibroblasts in the presence/absence of sgp130Fc.

Findings

We report that targeting IL-6 trans-signalling by sgp130Fc attenuated SARS-CoV-2-related clinical symptoms and mortality. In surviving mice, the treatment caused a significant decrease in lung damage. In vitro, IL-6 trans-signalling induced strong and persisting JAK1/STAT3 activation in endothelial cells and lung fibroblasts with proinflammatory effects, which were attenuated by sgp130Fc. Our data also suggest that in those cells with scant amounts of IL-6R, the induction of gp130 and IL-6 by IL-6:sIL-6R complex sustains IL-6 trans-signalling.

Interpretation

IL-6 trans-signalling fosters progression of COVID-19, and suggests that specific blockade of this signalling mode could offer a promising alternative to mitigate both short- and long-term consequences without affecting the beneficial effects of IL-6 classic signalling. These results have implications for the development of new therapies of lung injury and endotheliopathy in COVID-19.

Funding

The project was supported by ISCIII, Spain (COV-20/00792 to MB, PI23/01351 to MARH) and the European Commission-Next generation EU (European Union) (Regulation EU 2020/2094), through CSIC's Global Health Platform (PTI Salud Global, SGL2103029 to MB). PID2019-110587RB-I00 (MB) supported by MICIN/AEI/10.13039/501100011033/and PID2022-143034OB-I00 (MB) by MICIN/AEI/10.13039/501100011033/FEDER. MAR-H acknowledges support from ISCIII, Spain and the European Commission-Next generation EU (European Union), through CSIC's Global Health PTI.
2024-04-26 2024 other research-article; Journal Article abstract-available 10.1016/j.ebiom.2024.105132 Targeting IL-6 trans-signalling by sgp130Fc attenuates severity in SARS-CoV-2 -infected mice and reduces endotheliopathy. Rodríguez-Hernández MÁ, Baena-Bustos M, Carneros D, Zurita-Palomo C, Muñoz-Pinillos P, Millán J, Padillo FJ, Smerdou C, von Kobbe C, Rose-John S, Bustos M. EBioMedicine. 2024; 103
Potential long-term effects of SARS-CoV-2 infection on the pulmonary vasculature: Multilayered cross-talks in the setting of coinfections and comorbidities.
Kumar R, Aktay-Cetin Ö, Craddock V, Morales-Cano D, [...], Dhillon NK.
PLoS Pathog. 2023; 19 (1)
DOI: 10.1371/journal.ppat.1011063
The Coronavirus Disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and its sublineages pose a new challenge to healthcare systems worldwide due to its ability to efficiently spread in immunized populations and its resistance to currently available therapies. COVID-19, although targeting primarily the respiratory system, is also now well established that later affects every organ in the body. Most importantly, despite the available therapy and vaccine-elicited protection, the long-term consequences of viral infection in breakthrough and asymptomatic individuals are areas of concern. In the past two years, investigators accumulated evidence on how the virus triggers our immune system and the molecular signals involved in the cross-talk between immune cells and structural cells in the pulmonary vasculature to drive pathological lung complications such as endothelial dysfunction and thrombosis. In the review, we emphasize recent updates on the pathophysiological inflammatory and immune responses associated with SARS-CoV-2 infection and their potential long-term consequences that may consequently lead to the development of pulmonary vascular diseases.
2023-01-12 2023 other Research Support, Non-U.S. Gov't; review-article; Review; Journal Article; Research Support, N.I.H., Extramural abstract-available 10.1371/journal.ppat.1011063 Potential long-term effects of SARS-CoV-2 infection on the pulmonary vasculature: Multilayered cross-talks in the setting of coinfections and comorbidities. Kumar R, Aktay-Cetin Ö, Craddock V, Morales-Cano D, Kosanovic D, Cogolludo A, Perez-Vizcaino F, Avdeev S, Kumar A, Ram AK, Agarwal S, Chakraborty A, Savai R, de Jesus Perez V, Graham BB, Butrous G, Dhillon NK. PLoS Pathog. 2023; 19 (1)
Editorial: Host factors involved in viral infection.
Jimenez-Guardeño JM, Menéndez-Arias L, Betancor G.
Front Microbiol. 2024; 15
DOI: 10.3389/fmicb.2024.1382503
2024-03-11 2024 other Editorial 10.3389/fmicb.2024.1382503 Editorial: Host factors involved in viral infection. Jimenez-Guardeño JM, Menéndez-Arias L, Betancor G. Front Microbiol. 2024; 15
Inflammatory Polymorphisms (IL-6 rs1800796, IL-10 rs1800896, TNF-α rs1800629, and IFITM3 rs12252) Are Not Associated with Post-COVID Symptoms in Previously Hospitalized COVID-19 Survivors.
Fernández-de-Las-Peñas C, Díaz-Gil G, Gil-Crujera A, Gómez-Sánchez SM, [...], Giordano R.
Viruses. 2024; 16 (2)
DOI: 10.3390/v16020275
The aim of this study was to identify the association between four selected inflammatory polymorphisms with the development of long-term post-COVID symptoms in subjects who had been hospitalized due to SARS-CoV-2 infection during the first wave of the pandemic. These polymorphisms were selected as they are associated with severe COVID-19 disease and cytokine storm, so they could be important to prognoses post-COVID. A total of 408 (48.5% female, age: 58.5 ± 14.0 years) previously hospitalized COVID-19 survivors participated. The three potential genotypes of the following four single-nucleotide polymorphisms, IL-6 rs1800796, IL-10 rs1800896, TNF-α rs1800629, and IFITM3 rs12252, were obtained from non-stimulated saliva samples of the participants. The participants were asked to self-report the presence of any post-COVID symptoms (defined as symptoms that had started no later than one month after SARS-CoV-2 acute infection) and whether the symptoms persisted at the time of the study. At the time of the study (mean: 15.6, SD: 5.6 months after discharge), 89.4% of patients reported at least one post-COVID symptom (mean number of symptoms: 3.0; SD: 1.7). Fatigue (69.3%), pain (40.9%), and memory loss (27.2%) were the most prevalent post-COVID symptoms in the total sample. Overall, no differences in the post-COVID symptoms depending on the IL-6 rs1800796, IL-10 rs1800896, TNF-α rs1800629, and IFITM3 rs12252 genotypes were seen. The four SNPs assessed, albeit having been previously associated with inflammation and COVID-19 severity, did not cause a predisposition to the development of post-COVID symptoms in the previously hospitalized COVID-19 survivors.
2024-02-09 2024 other research-article; Journal Article abstract-available 10.3390/v16020275 Inflammatory Polymorphisms (IL-6 <i>rs1800796</i>, IL-10 <i>rs1800896</i>, TNF-α <i>rs1800629</i>, and IFITM3 <i>rs12252</i>) Are Not Associated with Post-COVID Symptoms in Previously Hospitalized COVID-19 Survivors. Fernández-de-Las-Peñas C, Díaz-Gil G, Gil-Crujera A, Gómez-Sánchez SM, Ambite-Quesada S, Torres-Macho J, Ryan-Murua P, Franco-Moreno AI, Pellicer-Valero OJ, Arendt-Nielsen L, Giordano R. Viruses. 2024; 16 (2)
Drugs for COVID-19: An Update.
Ceramella J, Iacopetta D, Sinicropi MS, Andreu I, [...], Catalano A.
Molecules. 2022; 27 (23)
DOI: 10.3390/molecules27238562
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was the seventh known human coronavirus, and it was identified in Wuhan, Hubei province, China, in 2020. It caused the highly contagious disease called coronavirus disease 2019 (COVID-19), declared a global pandemic by the World Health Organization (WHO) on 11 March 2020. A great number of studies in the search of new therapies and vaccines have been carried out in these three long years, producing a series of successes; however, the need for more effective vaccines, therapies and other solutions is still being pursued. This review represents a tracking shot of the current pharmacological therapies used for the treatment of COVID-19.
2022-12-05 2022 other review-article; Review; Journal Article abstract-available 10.3390/molecules27238562 Drugs for COVID-19: An Update. Ceramella J, Iacopetta D, Sinicropi MS, Andreu I, Mariconda A, Saturnino C, Giuzio F, Longo P, Aquaro S, Catalano A. Molecules. 2022; 27 (23)
COVID-19 signalome: Potential therapeutic interventions.
Lundstrom K, Hromić-Jahjefendić A, Bilajac E, Aljabali AAA, [...], Barh D.
Cell Signal. 2023; 103
DOI: 10.1016/j.cellsig.2022.110559
The COVID-19 pandemic has triggered intensive research and development of drugs and vaccines against SARS-CoV-2 during the last two years. The major success was especially observed with development of vaccines based on viral vectors, nucleic acids and whole viral particles, which have received emergent authorization leading to global mass vaccinations. Although the vaccine programs have made a big impact on COVID-19 spread and severity, emerging novel variants have raised serious concerns about vaccine efficacy. Due to the urgent demand, drug development had originally to rely on repurposing of antiviral drugs developed against other infectious diseases. For both drug and vaccine development the focus has been mainly on SARS-CoV-2 surface proteins and host cell receptors involved in viral attachment and entry. In this review, we expand the spectrum of SARS-CoV-2 targets by investigating the COVID-19 signalome. In addition to the SARS-CoV-2 Spike protein, the envelope, membrane, and nucleoprotein targets have been subjected to research. Moreover, viral proteases have presented the possibility to develop different strategies for the inhibition of SARS-CoV-2 replication and spread. Several signaling pathways involving the renin-angiotensin system, angiotensin-converting enzymes, immune pathways, hypoxia, and calcium signaling have provided attractive alternative targets for more efficient drug development.
2022-12-13 2022 other review-article; Review; Journal Article abstract-available 10.1016/j.cellsig.2022.110559 COVID-19 signalome: Potential therapeutic interventions. Lundstrom K, Hromić-Jahjefendić A, Bilajac E, Aljabali AAA, Baralić K, Sabri NA, Shehata EM, Raslan M, Raslan SA, Ferreira ACBH, Orlandi L, Serrano-Aroca Á, Uversky VN, Hassan SS, Redwan EM, Azevedo V, Alzahrani KJ, Alsharif KF, Halawani IF, Alzahrani FM, Tambuwala MM, Barh D. Cell Signal. 2023; 103
COVID-19 and lung involvement
You J, Faner R, Sibila O, Sellarés J.
Handbook of Systemic Autoimmune Diseases. 2022; 17
DOI:
In late December 2019, a novel coronavirus emerged and had a rapid and worldwide spread, resulting in an ongoing pandemic. This virus, designated SARS-CoV-2, causes a respiratory disease named COVID-19 which can range in severity, depending not only on the viral infection but also conditioned by the immune system and the host's response. COVID-19 is often associated with aggressive and uncontrolled inflammation that may lead to acute respiratory distress syndrome (ARDS), multiorgan damage and failure, and death. In this chapter, we review the general characteristics of SARS-CoV-2 infection, its interaction with target cells and the resulting immune response, as well as current and potential therapeutic interventions.
2022-01-01 2022 other Other abstract-available COVID-19 and lung involvement You J, Faner R, Sibila O, Sellarés J. Handbook of Systemic Autoimmune Diseases. 2022; 17
Harnessing and bioprospecting botanical-based herbal medicines against potential drug targets for COVID-19: a review coupled molecular docking studies.
Pal T, Anand U, Sikdar Mitra S, Biswas P, [...], Pérez de la Lastra JM.
J Biomol Struct Dyn. 2023;
DOI: 10.1080/07391102.2023.2187634
Since the end of February 2020, the world has come to a standstill due to the virus SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2). Since then, the global scientific community has explored various remedies and treatments against this virus, including natural products that have always been a choice because of their many benefits. Various known phytochemicals are well documented for their antiviral properties. Research is being carried out to discover new natural plant products or existing ones as a treatment measure for this disease. The three important targets in this regard are-papain like protease (PLpro), spike protein, and 3 chymotrypsin like proteases (3CLpro). Various docking studies are also being elucidated to identify the phytochemicals that modulate crucial proteins of the virus. The paper is simultaneously a comprehensive review that covers recent advances in the domain of the effect of various botanically derived natural products as an alternative treatment approach against Coronavirus Disease 2019 (COVID-19). Furthermore, the docking analyses revealed that rutin (inhibitor of the major protease of SARS-CoV-2), gallocatechin (e.g., interacting with 03 hydrogen bonds with a spike-like protein), lycorine (showing the best binding affinity with amino acids GLN498, THR500 and GLY446 of the spike-like protein), and quercetrin (inhabiting at its residues ASP216, PHE219, and ILE259) are promising inhibitors of SARS‑CoV‑2.Communicated by Ramaswamy H. Sarma.
2023-04-27 2023 other Review; Journal Article abstract-available 10.1080/07391102.2023.2187634 Harnessing and bioprospecting botanical-based herbal medicines against potential drug targets for COVID-19: a review coupled molecular docking studies. Pal T, Anand U, Sikdar Mitra S, Biswas P, Tripathi V, Proćków J, Dey A, Pérez de la Lastra JM. J Biomol Struct Dyn. 2023;
Gut Microbiota Dysbiosis in COVID-19: Modulation and Approaches for Prevention and Therapy.
Martín Giménez VM, Modrego J, Gómez-Garre D, Manucha W, [...], de Las Heras N.
Int J Mol Sci. 2023; 24 (15)
DOI: 10.3390/ijms241512249
Inflammation and oxidative stress are critical underlying mechanisms associated with COVID-19 that contribute to the complications and clinical deterioration of patients. Additionally, COVID-19 has the potential to alter the composition of patients' gut microbiota, characterized by a decreased abundance of bacteria with probiotic effects. Interestingly, certain strains of these bacteria produce metabolites that can target the S protein of other coronaviruses, thereby preventing their transmission and harmful effects. At the same time, the presence of gut dysbiosis can exacerbate inflammation and oxidative stress, creating a vicious cycle that perpetuates the disease. Furthermore, it is widely recognized that the gut microbiota can metabolize various foods and drugs, producing by-products that may have either beneficial or detrimental effects. In this regard, a decrease in short-chain fatty acid (SCFA), such as acetate, propionate, and butyrate, can influence the overall inflammatory and oxidative state, affecting the prevention, treatment, or worsening of COVID-19. This review aims to explore the current evidence regarding gut dysbiosis in patients with COVID-19, its association with inflammation and oxidative stress, the molecular mechanisms involved, and the potential of gut microbiota modulation in preventing and treating SARS-CoV-2 infection. Given that gut microbiota has demonstrated high adaptability, exploring ways and strategies to maintain good intestinal health, as well as an appropriate diversity and composition of the gut microbiome, becomes crucial in the battle against COVID-19.
2023-07-31 2023 other review-article; Review; Journal Article abstract-available 10.3390/ijms241512249 Gut Microbiota Dysbiosis in COVID-19: Modulation and Approaches for Prevention and Therapy. Martín Giménez VM, Modrego J, Gómez-Garre D, Manucha W, de Las Heras N. Int J Mol Sci. 2023; 24 (15)
The Role of Host Cell Glycans on Virus Infectivity: The SARS-CoV-2 Case.
Acosta-Gutiérrez S, Buckley J, Battaglia G.
Adv Sci (Weinh). 2022;
DOI: 10.1002/advs.202201853
Glycans are ubiquitously expressed sugars, coating the cell and protein surfaces. They are found on many proteins as either short and branched chains or long chains sticking out from special membrane proteins, known as proteoglycans. This sugar cushion, the glycocalyx, modulates specific interactions and protects the cell. Here it is shown that both the expression of proteoglycans and the glycans expressed on the surface of both the host and virus proteins have a critical role in modulating viral attachment to the cell. A mathematical model using SARS-Cov-2 as an archetypical virus to study the glycan role during infection is proposed. It is shown that this occurs via a tug-of-war of forces. On one side, the multivalent molecular recognition that viral proteins have toward specific host glycans and receptors. On the other side, the glycan steric repulsion that a virus must overcome to approach such specific receptors. By balancing both interactions, viral tropism can be predicted. In other words, the authors can map out the cells susceptible to virus infection in terms of receptors and proteoglycans compositions.
2022-11-23 2022 other research-article; Journal Article abstract-available 10.1002/advs.202201853 The Role of Host Cell Glycans on Virus Infectivity: The SARS-CoV-2 Case. Acosta-Gutiérrez S, Buckley J, Battaglia G. Adv Sci (Weinh). 2022;
Using PyMOL to Understand Why COVID-19 Vaccines Save Lives.
Maya C.
J Chem Educ. 2023; 100 (3)
DOI: 10.1021/acs.jchemed.2c00779
Chemistry and biochemistry instructors must help students to develop the ability to visualize and manipulate 3D biomolecular structures and critically analyze them and their relationship to their functions. To do this, representative systems must be strategically selected to stimulate students' motivation. Since the World Health Organization declared a global pandemic caused by a new beta-coronavirus, called SARS-CoV-2 in early 2020, huge efforts are being taken by researchers to learn in depth how this virus works and a lot of scientific results are continuously reported. Many of them focus on the structural features of the viral spike glycoprotein and their relation with the vaccine development. This paper presents a series of workouts that deep into the structural characteristics of the spike protein S SARS-CoV-2 virus and the structural features involved in its infection process, using free online resources such as the PDB and the computer program PyMOL. This type of activity is intended to engage structural biology students in examining these macromolecules and others to help establish procedures for controlling COVID-19 and other future infectious diseases. PyMOL session files and student activities are provided.
2023-02-28 2023 other research-article; Journal Article abstract-available 10.1021/acs.jchemed.2c00779 Using PyMOL to Understand Why COVID-19 Vaccines Save Lives. Maya C. J Chem Educ. 2023; 100 (3)
Development and Validation of a Highly Sensitive Multiplex Immunoassay for SARS-CoV-2 Humoral Response Monitorization: A Study of the Antibody Response in COVID-19 Patients with Different Clinical Profiles during the First and Second Waves in Cadiz, Spain.
Olvera-Collantes L, Moares N, Fernandez-Cisnal R, Muñoz-Miranda JP, [...], Garcia-Cozar F.
Microorganisms. 2023; 11 (12)
DOI: 10.3390/microorganisms11122997
There is still a long way ahead regarding the COVID-19 pandemic, since emerging waves remain a daunting challenge to the healthcare system. For this reason, the development of new preventive tools and therapeutic strategies to deal with the disease have been necessary, among which serological assays have played a key role in the control of COVID-19 outbreaks and vaccine development. Here, we have developed and evaluated an immunoassay capable of simultaneously detecting multiple IgG antibodies against different SARS-CoV-2 antigens through the use of Bio-PlexTM technology. Additionally, we have analyzed the antibody response in COVID-19 patients with different clinical profiles in Cadiz, Spain. The multiplex immunoassay presented is a high-throughput and robust immune response monitoring tool capable of concurrently detecting anti-S1, anti-NC and anti-RBD IgG antibodies in serum with a very high sensitivity (94.34-97.96%) and specificity (91.84-100%). Therefore, the immunoassay proposed herein may be a useful monitoring tool for individual humoral immunity against SARS-CoV-2, as well as for epidemiological surveillance. In addition, we show the values of antibodies against multiple SARS-CoV-2 antigens and their correlation with the different clinical profiles of unvaccinated COVID-19 patients in Cadiz, Spain, during the first and second waves of the pandemic.
2023-12-16 2023 other research-article; Journal Article abstract-available 10.3390/microorganisms11122997 Development and Validation of a Highly Sensitive Multiplex Immunoassay for SARS-CoV-2 Humoral Response Monitorization: A Study of the Antibody Response in COVID-19 Patients with Different Clinical Profiles during the First and Second Waves in Cadiz, Spain. Olvera-Collantes L, Moares N, Fernandez-Cisnal R, Muñoz-Miranda JP, Gonzalez-Garcia P, Gabucio A, Freyre-Carrillo C, Jordan-Chaves JD, Trujillo-Soto T, Rodriguez-Martinez MP, Martin-Rubio MI, Escuer E, Rodriguez-Iglesias M, Fernandez-Ponce C, Garcia-Cozar F. Microorganisms. 2023; 11 (12)
The Finding of the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) in a Wild Eurasian River Otter (Lutra lutra) Highlights the Need for Viral Surveillance in Wild Mustelids.
Padilla-Blanco M, Aguiló-Gisbert J, Rubio V, Lizana V, [...], Rubio-Guerri C.
Front Vet Sci. 2022; 9
DOI: 10.3389/fvets.2022.826991
Animals have been involved in the three known outbreaks of severe respiratory syndromes due to coronaviruses (years 2005, 2012, and 2019). The pandemic nature of the SARS-CoV-2 outbreak increases the likelihood of infection from humans of susceptible animal species that, thus, could become secondary viral hosts and even disease reservoirs. We present evidence of spillover infection of wild mustelids by reporting the presence of SARS-CoV-2 in a Eurasian river otter found near a water reservoir in the Valencian Community (Spain). We detected the virus using two different commercial RTqPCR assays on RNA extracted from the nasopharynx (swabbing) and from lung tissue and mediastinal lymph node homogenates. The corresponding samples from two additional otters from distant sites tested negative in identical assays. The diagnosis in the positive otter was confirmed by two-tube RT-PCR assay in which RNA was first retrotranscribed, and then specific regions of the spike (S), nucleocapsid (N), and ORF10 genes were separately amplified from the produced cDNA, followed by electrophoretic visualization and Sanger sequencing. The sequences of the amplified products revealed some non-synonymous changes in the N and ORF10 partial sequences, relative to the consensus sequence. These changes, identified already in human patient samples, point to human origin of the virus, although their specific combination was unique. These findings, together with our previous report of SARS-CoV-2 infection of feral American mink, highlight the need for SARS-CoV-2 surveillance of wild or feral mustelids to evaluate the risk that these animals could become SARS-CoV-2 reservoirs.
2022-03-31 2022 other brief-report; Journal Article abstract-available 10.3389/fvets.2022.826991 The Finding of the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) in a Wild Eurasian River Otter (<i>Lutra lutra</i>) Highlights the Need for Viral Surveillance in Wild Mustelids. Padilla-Blanco M, Aguiló-Gisbert J, Rubio V, Lizana V, Chillida-Martínez E, Cardells J, Maiques E, Rubio-Guerri C. Front Vet Sci. 2022; 9
SARSMutOnto: An Ontology for SARS-CoV-2 Lineages and Mutations.
Bakkas J, Hanine M, Chekry A, Gounane S, [...], Ashraf I.
Viruses. 2023; 15 (2)
DOI: 10.3390/v15020505
Mutations allow viruses to continuously evolve by changing their genetic code to adapt to the hosts they infect. It is an adaptive and evolutionary mechanism that helps viruses acquire characteristics favoring their survival and propagation. The COVID-19 pandemic declared by the WHO in March 2020 is caused by the SARS-CoV-2 virus. The non-stop adaptive mutations of this virus and the emergence of several variants over time with characteristics favoring their spread constitute one of the biggest obstacles that researchers face in controlling this pandemic. Understanding the mutation mechanism allows for the adoption of anticipatory measures and the proposal of strategies to control its propagation. In this study, we focus on the mutations of this virus, and we propose the SARSMutOnto ontology to model SARS-CoV-2 mutations reported by Pango researchers. A detailed description is given for each mutation. The genes where the mutations occur and the genomic structure of this virus are also included. The sub-lineages and the recombinant sub-lineages resulting from these mutations are additionally represented while maintaining their hierarchy. We developed a Python-based tool to automatically generate this ontology from various published Pango source files. At the end of this paper, we provide some examples of SPARQL queries that can be used to exploit this ontology. SARSMutOnto might become a 'wet bench' machine learning tool for predicting likely future mutations based on previous mutations.
2023-02-11 2023 other Research Support, Non-U.S. Gov't; research-article; Journal Article abstract-available 10.3390/v15020505 SARSMutOnto: An Ontology for SARS-CoV-2 Lineages and Mutations. Bakkas J, Hanine M, Chekry A, Gounane S, de la Torre Díez I, Lipari V, López NMM, Ashraf I. Viruses. 2023; 15 (2)
Molecular and Serological Studies on Potential SARS-CoV-2 Infection among 43 Lemurs under Human Care-Evidence for Past Infection in at Least One Individual.
Musoles-Cuenca B, Aguiló-Gisbert J, Lorenzo-Bermejo T, Canales R, [...], Rubio-Guerri C.
Animals (Basel). 2023; 14 (1)
DOI: 10.3390/ani14010140
In the setting of the recent COVID-19 pandemic, transmission of SARS-CoV-2 to animals has been reported in both domestic and wild animals and is a matter of concern. Given the genetic and functional similarities to humans, non-human primates merit particular attention. In the case of lemurs, generally considered endangered, they are believed to be susceptible to SARS-CoV-2 infection. We have conducted a study for evidence of SARS-CoV-2 infection among the 43 lemurs of Mundomar, a zoological park in Benidorm, Spain. They belong to two endangered lemur species, 23 black-and-white ruffed lemurs (Varecia variegata) and 20 ring-tailed lemurs (Lemur catta). Health assessments conducted in 2022 and 2023 included molecular analyses for SARS-CoV-2 RNA of oral and rectal swabs using two different RT-qPCR assays, always with negative results for SARS-CoV-2 in all animals. The assessment also included serological testing for antibodies against the receptor-binding domain (RBD) of the spike protein (S) of SARS-CoV-2, which again yielded negative results in all animals except one black-and-white ruffed lemur, supporting prior infection of that animal with SARS-CoV-2. Our data, while not indicating a high susceptibility of lemurs to SARS-CoV-2 infection, show that they can be infected, adding to the existing information body on potential ways for SARS-CoV-2 virus spreading in zoos, highlighting the need for animal surveillance for the virus.
2023-12-31 2023 other brief-report; Journal Article abstract-available 10.3390/ani14010140 Molecular and Serological Studies on Potential SARS-CoV-2 Infection among 43 Lemurs under Human Care-Evidence for Past Infection in at Least One Individual. Musoles-Cuenca B, Aguiló-Gisbert J, Lorenzo-Bermejo T, Canales R, Ballester B, Romani-Cremaschi U, Martínez-Valverde R, Maiques E, Marteles D, Rueda P, Rubio V, Villanueva-Saz S, Rubio-Guerri C. Animals (Basel). 2023; 14 (1)
Bacterial Artificial Chromosome Reverse Genetics Approaches for SARS-CoV-2.
Chiem K, Nogales A, Almazán F, Ye C, [...], Martínez-Sobrido L.
Methods Mol Biol. 2024; 2733
DOI: 10.1007/978-1-0716-3533-9_9
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new member of the Coronaviridae family responsible for the coronavirus disease 19 (COVID-19) pandemic. To date, SARS-CoV-2 has been accountable for over 624 million infection cases and more than 6.5 million human deaths. The development and implementation of SARS-CoV-2 reverse genetics approaches have allowed researchers to genetically engineer infectious recombinant (r)SARS-CoV-2 to answer important questions in the biology of SARS-CoV-2 infection. Reverse genetics techniques have also facilitated the generation of rSARS-CoV-2 expressing reporter genes to expedite the identification of compounds with antiviral activity in vivo and in vitro. Likewise, reverse genetics has been used to generate attenuated forms of the virus for their potential implementation as live-attenuated vaccines (LAV) for the prevention of SARS-CoV-2 infection. Here we describe the experimental procedures for the generation of rSARS-CoV-2 using a well-established and robust bacterial artificial chromosome (BAC)-based reverse genetics system. The protocol allows to produce wild-type and mutant rSARS-CoV-2 that can be used to understand the contribution of viral proteins and/or amino acid residues in viral replication and transcription, pathogenesis and transmission, and interaction with cellular host factors.
2024-01-01 2024 other Journal Article abstract-available 10.1007/978-1-0716-3533-9_9 Bacterial Artificial Chromosome Reverse Genetics Approaches for SARS-CoV-2. Chiem K, Nogales A, Almazán F, Ye C, Martínez-Sobrido L. Methods Mol Biol. 2024; 2733
Inhaled corticosteroids for the treatment of COVID-19.
Bafadhel M, Faner R, Taillé C, Russell REK, [...], Agustí A.
Eur Respir Rev. 2022; 31 (166)
DOI: 10.1183/16000617.0099-2022
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has caused severe illness and mortality for millions worldwide. Despite the development, approval and rollout of vaccination programmes globally to prevent infection by SARS-CoV-2 and the development of coronavirus disease 2019 (COVID-19), treatments are still urgently needed to improve outcomes. Early in the pandemic it was observed that patients with pre-existing asthma or COPD were underrepresented among those with COVID-19. Evidence from clinical studies indicates that the inhaled corticosteroids (ICS) routinely taken for asthma and COPD could have had a protective role in preventing severe COVID-19 and, therefore, may be a promising treatment for COVID-19. This review summarises the evidence supporting the beneficial effects of ICS on outcomes in patients with COVID-19 and explores the potential protective mechanisms.
2022-11-29 2022 other review-article; Review; Journal Article abstract-available 10.1183/16000617.0099-2022 Inhaled corticosteroids for the treatment of COVID-19. Bafadhel M, Faner R, Taillé C, Russell REK, Welte T, Barnes PJ, Agustí A. Eur Respir Rev. 2022; 31 (166)
SARS-CoV-2 accessory proteins involvement in inflammatory and profibrotic processes through IL11 signaling.
López-Ayllón BD, de Lucas-Rius A, Mendoza-García L, García-García T, [...], Montoya M.
Front Immunol. 2023; 14
DOI: 10.3389/fimmu.2023.1220306
SARS-CoV-2, the cause of the COVID-19 pandemic, possesses eleven accessory proteins encoded in its genome. Their roles during infection are still not completely understood. In this study, transcriptomics analysis revealed that both WNT5A and IL11 were significantly up-regulated in A549 cells expressing individual accessory proteins ORF6, ORF8, ORF9b or ORF9c from SARS-CoV-2 (Wuhan-Hu-1 isolate). IL11 is a member of the IL6 family of cytokines. IL11 signaling-related genes were also differentially expressed. Bioinformatics analysis disclosed that both WNT5A and IL11 were involved in pulmonary fibrosis idiopathic disease and functional assays confirmed their association with profibrotic cell responses. Subsequently, data comparison with lung cell lines infected with SARS-CoV-2 or lung biopsies from patients with COVID-19, evidenced altered profibrotic gene expression that matched those obtained in this study. Our results show ORF6, ORF8, ORF9b and ORF9c involvement in inflammatory and profibrotic responses. Thus, these accessory proteins could be targeted by new therapies against COVID-19 disease.
2023-07-20 2023 other Research Support, Non-U.S. Gov't; research-article; Journal Article abstract-available 10.3389/fimmu.2023.1220306 SARS-CoV-2 accessory proteins involvement in inflammatory and profibrotic processes through IL11 signaling. López-Ayllón BD, de Lucas-Rius A, Mendoza-García L, García-García T, Fernández-Rodríguez R, Suárez-Cárdenas JM, Santos FM, Corrales F, Redondo N, Pedrucci F, Zaldívar-López S, Jiménez-Marín Á, Garrido JJ, Montoya M. Front Immunol. 2023; 14
Genomic determinants of Furin cleavage in diverse European SARS-related bat coronaviruses.
Sander AL, Moreira-Soto A, Yordanov S, Toplak I, [...], Drexler JF.
Commun Biol. 2022; 5 (1)
DOI: 10.1038/s42003-022-03421-w
The furin cleavage site (FCS) in SARS-CoV-2 is unique within the Severe acute respiratory syndrome-related coronavirus (SrC) species. We re-assessed diverse SrC from European horseshoe bats and analyzed the spike-encoding genomic region harboring the FCS in SARS-CoV-2. We reveal molecular features in SrC such as purine richness and RNA secondary structures that resemble those required for FCS acquisition in avian influenza viruses. We discuss the potential acquisition of FCS through molecular mechanisms such as nucleotide substitution, insertion, or recombination, and show that a single nucleotide exchange in two European bat-associated SrC may suffice to enable furin cleavage. Furthermore, we show that FCS occurrence is variable in bat- and rodent-borne counterparts of human coronaviruses. Our results suggest that furin cleavage sites can be acquired in SrC via conserved molecular mechanisms known in other reservoir-bound RNA viruses and thus support a natural origin of SARS-CoV-2.
2022-05-30 2022 other Research Support, Non-U.S. Gov't; research-article; Journal Article abstract-available 10.1038/s42003-022-03421-w Genomic determinants of Furin cleavage in diverse European SARS-related bat coronaviruses. Sander AL, Moreira-Soto A, Yordanov S, Toplak I, Balboni A, Ameneiros RS, Corman V, Drosten C, Drexler JF. Commun Biol. 2022; 5 (1)
Benchmarking ANI potentials as a rescoring function and screening FDA drugs for SARS-CoV-2 Mpro.
Zengin IN, Koca MS, Tayfuroglu O, Yildiz M, [...], Kocak A.
J Comput Aided Mol Des. 2024; 38 (1)
DOI: 10.1007/s10822-024-00554-4
Here, we introduce the use of ANI-ML potentials as a rescoring function in the host-guest interaction in molecular docking. Our results show that the "docking power" of ANI potentials can compete with the current scoring functions at the same level of computational cost. Benchmarking studies on CASF-2016 dataset showed that ANI is ranked in the top 5 scoring functions among the other 34 tested. In particular, the ANI predicted interaction energies when used in conjunction with GOLD-PLP scoring function can boost the top ranked solution to be the closest to the x-ray structure. Rapid and accurate calculation of interaction energies between ligand and protein also enables screening of millions of drug candidates/docking poses. Using a unique protocol in which docking by GOLD-PLP, rescoring by ANI-ML potentials and extensive MD simulations along with end state free energy methods are combined, we have screened FDA approved drugs against the SARS-CoV-2 main protease (Mpro). The top six drug molecules suggested by the consensus of these free energy methods have already been in clinical trials or proposed as potential drug molecules in previous theoretical and experimental studies, approving the validity and the power of accuracy in our screening method.
2024-03-27 2024 other research-article; Journal Article abstract-available 10.1007/s10822-024-00554-4 Benchmarking ANI potentials as a rescoring function and screening FDA drugs for SARS-CoV-2 M<sup>pro</sup>. Zengin IN, Koca MS, Tayfuroglu O, Yildiz M, Kocak A. J Comput Aided Mol Des. 2024; 38 (1)
Long COVID or Post-COVID-19 Condition: Past, Present and Future Research Directions.
Fernández-de-Las-Peñas C, Raveendran AV, Giordano R, Arendt-Nielsen L.
Microorganisms. 2023; 11 (12)
DOI: 10.3390/microorganisms11122959
The presence of symptoms after an acute SARS-CoV-2 infection (long-COVID) has become a worldwide healthcare emergency but remains underestimated and undertreated due to a lack of recognition of the condition and knowledge of the underlying mechanisms. In fact, the prevalence of post-COVID symptoms ranges from 50% during the first months after the infection up to 20% two-years after. This perspective review aimed to map the existing literature on post-COVID symptoms and to identify gaps in the literature to guide the global effort toward an improved understanding of long-COVID and suggest future research directions. There is a plethora of symptomatology that can be due to COVID-19; however, today, there is no clear classification and definition of this condition, termed long-COVID or post-COVID-19 condition. The heterogeneity in the symptomatology has led to the presence of groups/clusters of patients, which could exhibit different risk factors and different mechanisms. Viral persistence, long-lasting inflammation, immune dysregulation, autoimmune reactions, reactivation of latent infections, endothelial dysfunction and alteration in gut microbiota have been proposed as potential mechanisms explaining the complexity of long-COVID. In such an equation, viral biology (e.g., re-infections, SARS-CoV-2 variants), host biology (e.g., genetics, epigenetics) and external factors (e.g., vaccination) should be also considered. These various factors will be discussed in the current perspective review and future directions suggested.
2023-12-11 2023 other review-article; Review; Journal Article abstract-available 10.3390/microorganisms11122959 Long COVID or Post-COVID-19 Condition: Past, Present and Future Research Directions. Fernández-de-Las-Peñas C, Raveendran AV, Giordano R, Arendt-Nielsen L. Microorganisms. 2023; 11 (12)
Ultrasensitive detection of SARS-CoV-2 spike protein by graphene field-effect transistors.
Silvestri A, Zayas-Arrabal J, Vera-Hidalgo M, Di Silvio D, [...], Criado A.
Nanoscale. 2023; 15 (3)
DOI: 10.1039/d2nr05103f
COVID-19, caused by the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), originated a global health crisis, causing over 2 million casualties and altering human daily life all over the world. This pandemic emergency revealed the limitations of current diagnostic tests, highlighting the urgency to develop faster, more precise and sensitive sensors. Graphene field effect transistors (GFET) are analytical platforms that enclose all these requirements. However, the design of a sensitive and robust GFET is not a straightforward objective. In this work, we report a GFET array biosensor for the detection of SARS-CoV-2 spike protein using the human membrane protein involved in the virus internalisation: angiotensin-converting enzyme 2 (ACE2). By finely controlling the graphene functionalisation, by tuning the Debye length, and by deeply characterising the ACE2-spike protein interactions, we have been able to detect the target protein with an extremely low limit of detection (2.94 aM). This work set the basis for a new class of analytical platforms, based on human membrane proteins, with the potential to detect a broad variety of pathogens, even before their isolation, being a powerful tool in the fight against future pandemics.
2023-01-19 2023 other Journal Article abstract-available 10.1039/d2nr05103f Ultrasensitive detection of SARS-CoV-2 spike protein by graphene field-effect transistors. Silvestri A, Zayas-Arrabal J, Vera-Hidalgo M, Di Silvio D, Wetzl C, Martinez-Moro M, Zurutuza A, Torres E, Centeno A, Maestre A, Gómez JM, Arrastua M, Elicegui M, Ontoso N, Prato M, Coluzza I, Criado A. Nanoscale. 2023; 15 (3)
Challenges in distinguishing functional proteins from polyproteins in databases: implications for drug discovery.
Llop-Peiró A, Pujadas G, Garcia-Vallvé S.
Brief Bioinform. 2024; 25 (2)
DOI: 10.1093/bib/bbae012
This opinion article addresses a major issue in molecular biology and drug discovery by highlighting the complications that arise from combining polyproteins and their functional products within the same database entry. This problem, exemplified by the discovery of novel inhibitors for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease, has an influence on our ability to retrieve precise data and hinders the development of targeted therapies. It also emphasizes the need for improved database practices and underscores their significance in advancing scientific research. Furthermore, it emphasizes the need of learning from the SARS-CoV-2 pandemic in order to improve global preparedness for future health crises.
2024-01-01 2024 other research-article; Journal Article abstract-available 10.1093/bib/bbae012 Challenges in distinguishing functional proteins from polyproteins in databases: implications for drug discovery. Llop-Peiró A, Pujadas G, Garcia-Vallvé S. Brief Bioinform. 2024; 25 (2)
Peptidyl nitroalkene inhibitors of main protease rationalized by computational and crystallographic investigations as antivirals against SARS-CoV-2.
Medrano FJ, de la Hoz-Rodríguez S, Martí S, Arafet K, [...], González FV.
Commun Chem. 2024; 7 (1)
DOI: 10.1038/s42004-024-01104-7
The coronavirus disease 2019 (COVID-19) pandemic continues to represent a global public health issue. The viral main protease (Mpro) represents one of the most attractive targets for the development of antiviral drugs. Herein we report peptidyl nitroalkenes exhibiting enzyme inhibitory activity against Mpro (Ki: 1-10 μM) good anti-SARS-CoV-2 infection activity in the low micromolar range (EC50: 1-12 μM) without significant toxicity. Additional kinetic studies of compounds FGA145, FGA146 and FGA147 show that all three compounds inhibit cathepsin L, denoting a possible multitarget effect of these compounds in the antiviral activity. Structural analysis shows the binding mode of FGA146 and FGA147 to the active site of the protein. Furthermore, our results illustrate that peptidyl nitroalkenes are effective covalent reversible inhibitors of the Mpro and cathepsin L, and that inhibitors FGA145, FGA146 and FGA147 prevent infection against SARS-CoV-2.
2024-01-18 2024 other research-article; Journal Article abstract-available 10.1038/s42004-024-01104-7 Peptidyl nitroalkene inhibitors of main protease rationalized by computational and crystallographic investigations as antivirals against SARS-CoV-2. Medrano FJ, de la Hoz-Rodríguez S, Martí S, Arafet K, Schirmeister T, Hammerschmidt SJ, Müller C, González-Martínez Á, Santillana E, Ziebuhr J, Romero A, Zimmer C, Weldert A, Zimmermann R, Lodola A, Świderek K, Moliner V, González FV. Commun Chem. 2024; 7 (1)
Perinatal Outcomes at Birth in Women Infected and Non-Infected with SARS-CoV-2: A Retrospective Study.
Vila-Candel R, Martin-Arribas A, Castro-Sánchez E, Escuriet R, [...], Martin-Moreno JM.
Healthcare (Basel). 2023; 11 (21)
DOI: 10.3390/healthcare11212833

Background

Coronavirus disease 2019 (COVID-19) was declared as a pandemic and public health emergency on 11 March 2020 by the World Health Organization. Different clinical trials on the efficacy of mRNA vaccination have excluded pregnant women, leading to a lack of empirical evidence on the efficacy of the vaccine in this population. The aim of the study was to examine the association between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection at birth and adverse perinatal outcomes in infected and non-infected women from a university hospital in Spain.

Methods

The data were obtained from electronic health records from 1 March 2020 to 28 February 2022. A bivariate descriptive analysis was performed, comparing women with and without confirmed SARS-CoV-2 infection during pregnancy using the chi-square test. A multivariate logistic regression was complementarily conducted to determine whether SARS-CoV-2 infection increases the risk of adverse obstetric and perinatal outcomes.

Results

A total of 2676 women were divided into two groups: non-infected with SARS-CoV-2 (n = 2624) and infected with SARS-CoV-2 (n = 52). Infected women were primarily multiparous (p < 0.03) and had received an incomplete vaccination regimen (p < 0.001). A greater incidence of premature rupture of membranes (p < 0.04) was observed among the non-infected women. Pertaining to perinatal outcomes, there was a notable rise in NICU admissions (p < 0.014), coupled with an extended duration of stay (p < 0.04), for neonates born to infected mothers in comparison to their non-infected counterparts.

Conclusion

Although SARS-CoV-2 infection may pose significant risks to pregnant women and their infants, adverse obstetrical/puerperal outcomes do not significantly differ between women infected and non-infected to SARS-CoV-2 in our study. NICU admissions were higher for neonates born to infected mothers. Additionally, coronavirus disease 2019 vaccination during pregnancy is not associated with severe adverse perinatal outcomes.
2023-10-27 2023 other research-article; Journal Article abstract-available 10.3390/healthcare11212833 Perinatal Outcomes at Birth in Women Infected and Non-Infected with SARS-CoV-2: A Retrospective Study. Vila-Candel R, Martin-Arribas A, Castro-Sánchez E, Escuriet R, Martin-Moreno JM. Healthcare (Basel). 2023; 11 (21)
Incipient functional SARS-CoV-2 diversification identified through neural network haplotype maps.
Delgado S, Somovilla P, Ferrer-Orta C, Martínez-González B, [...], Domingo E.
Proc Natl Acad Sci U S A. 2024; 121 (10)
DOI: 10.1073/pnas.2317851121
Since its introduction in the human population, SARS-CoV-2 has evolved into multiple clades, but the events in its intrahost diversification are not well understood. Here, we compare three-dimensional (3D) self-organized neural haplotype maps (SOMs) of SARS-CoV-2 from thirty individual nasopharyngeal diagnostic samples obtained within a 19-day interval in Madrid (Spain), at the time of transition between clades 19 and 20. SOMs have been trained with the haplotype repertoire present in the mutant spectra of the nsp12- and spike (S)-coding regions. Each SOM consisted of a dominant neuron (displaying the maximum frequency), surrounded by a low-frequency neuron cloud. The sequence of the master (dominant) neuron was either identical to that of the reference Wuhan-Hu-1 genome or differed from it at one nucleotide position. Six different deviant haplotype sequences were identified among the master neurons. Some of the substitutions in the neural clouds affected critical sites of the nsp12-nsp8-nsp7 polymerase complex and resulted in altered kinetics of RNA synthesis in an in vitro primer extension assay. Thus, the analysis has identified mutations that are relevant to modification of viral RNA synthesis, present in the mutant clouds of SARS-CoV-2 quasispecies. These mutations most likely occurred during intrahost diversification in several COVID-19 patients, during an initial stage of the pandemic, and within a brief time period.
2024-02-28 2024 other research-article; Journal Article abstract-available 10.1073/pnas.2317851121 Incipient functional SARS-CoV-2 diversification identified through neural network haplotype maps. Delgado S, Somovilla P, Ferrer-Orta C, Martínez-González B, Vázquez-Monteagudo S, Muñoz-Flores J, Soria ME, García-Crespo C, de Ávila AI, Durán-Pastor A, Gadea I, López-Galíndez C, Moran F, Lorenzo-Redondo R, Verdaguer N, Perales C, Domingo E. Proc Natl Acad Sci U S A. 2024; 121 (10)
Rapid and Accurate Detection of the SARS-CoV-2 Omicron Variant with a CRISPR-Cas12a Reaction in the RT-qPCR Pot.
Ruiz R, Montagud-Martínez R, Dorta-Gorrín A, Pablo-Marcos D, [...], Rodrigo G.
ACS Omega. 2024; 9 (16)
DOI: 10.1021/acsomega.3c09717
Gene sequencing in back of reverse transcription-quantitative polymerase chain reaction (RT-qPCR) is the current approach for discriminating infections produced by different severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants in the clinic. However, sequencing is often a time-consuming step, which hinders the deployment of a very fast response during a pandemic. Here, we propose to run a CRISPR-Cas12a reaction after completing the RT-qPCR and in the very same pot to detect with high specificity genetic marks characterizing variants of concern. A crRNA was appropriately designed to detect the S gene of the SARS-CoV-2 Omicron BA.1 variant. A significant response with >20-fold dynamic range was obtained for the Omicron BA.1 S gene, while the Delta S gene did not produce any detectable signal. The sensitivity of the method was analyzed with a series of diluted samples and different Cas12a nucleases. A correlation between the RT-qPCR CT values and the CRISPR-Cas12a reaction signals was observed. Variant discrimination with the CRISPR-Cas12a reaction was possible in some minutes with high accuracy from patient samples. In conclusion, CRISPR-Cas systems seem ready to be exploited in the clinic to boost personalized diagnoses and accelerate epidemiological surveillance in a cost-effective way.
2024-04-11 2024 other research-article; Journal Article abstract-available 10.1021/acsomega.3c09717 Rapid and Accurate Detection of the SARS-CoV-2 Omicron Variant with a CRISPR-Cas12a Reaction in the RT-qPCR Pot. Ruiz R, Montagud-Martínez R, Dorta-Gorrín A, Pablo-Marcos D, Gozalo M, Calvo-Montes J, Navas J, Rodrigo G. ACS Omega. 2024; 9 (16)
Recapping the Features of SARS-CoV-2 and Its Main Variants: Status and Future Paths.
Ortega MA, García-Montero C, Fraile-Martinez O, Colet P, [...], Sarría-Santamera A.
J Pers Med. 2022; 12 (6)
DOI: 10.3390/jpm12060995
Over the two years that we have been experiencing the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) pandemic, our challenges have been the race to develop vaccines and the difficulties in fighting against new variants due to the rapid ability of the virus to evolve. In this sense, different organizations have identified and classified the different variants that have been emerging, distinguishing between variants of concern (VOC), variants of interest (VOI), or variants under monitoring (VUM). The following review aims to describe the latest updates focusing on VOC and already de-escalated variants, as well as to describe the impact these have had on the global situation. Understanding the intrinsic properties of SARS-CoV-2 and its interaction with the immune system and vaccination is essential to make out the underlying mechanisms that have led to the appearance of these variants, helping to determine the next steps for better public management of this pandemic.
2022-06-18 2022 other review-article; Review; Journal Article abstract-available 10.3390/jpm12060995 Recapping the Features of SARS-CoV-2 and Its Main Variants: Status and Future Paths. Ortega MA, García-Montero C, Fraile-Martinez O, Colet P, Baizhaxynova A, Mukhtarova K, Alvarez-Mon M, Kanatova K, Asúnsolo A, Sarría-Santamera A. J Pers Med. 2022; 12 (6)
Humoral immune response to SARS-CoV-2 and endemic coronaviruses in urban and indigenous children in Colombia.
Fernández Villalobos NV, Marsall P, Torres Páez JC, Strömpl J, [...], Kann S.
Commun Med (Lond). 2023; 3 (1)
DOI: 10.1038/s43856-023-00376-9

Background

Although anti-SARS-CoV-2 humoral immune responses and epidemiology have been extensively studied, data gaps remain for certain populations such as indigenous people or children especially in low- and middle-income countries. To address this gap, we evaluated SARS-CoV-2 seroprevalence and humoral immunity towards the parental B.1 strain, local SARS-CoV-2 variants, and endemic coronaviruses in children from Colombia from March to April 2021.

Methods

We performed a cross-sectional seroprevalence study with 80 children from Bogotá and expanded our analysis by comparing results with an independent observational study of 82 children from the Wiwa community living in the north-eastern Colombian territories. Antibody IgG titers towards SARS-CoV-2 and the endemic coronaviruses as well as ACE2 binding inhibition as a proxy for neutralization towards several SARS-CoV-2 variants were analyzed using two multiplex-based immunoassays.

Results

While we find seroprevalence estimates of 21.3% in children from Bogotá, seroprevalence is higher with 34.1% in Wiwa children. We observe a robust induction of antibodies towards the surface-exposed spike protein, its S1-, S2- and receptor-binding-subdomains in all SARS-CoV-2 seropositive children. Only nucleocapsid-specific IgG is significantly lower in the indigenous participants. ACE2 binding inhibition is low for all SARS-CoV-2 variants examined. We observe a dominance of NL63 S1 IgG levels in urban and indigenous children which suggests an early exposure to this respiratory virus independent of living conditions and geographic location. SARS-CoV-2 seropositivity does not correlate with antibody levels towards any of the four endemic coronaviruses indicating the absence of cross-protective immunity.

Conclusions

Overall, antibody titers, but in particular ACE2 binding inhibition are low within Colombian samples, requiring further investigation to determine any potential clinical significance.
2023-10-20 2023 other research-article; Journal Article abstract-available 10.1038/s43856-023-00376-9 Humoral immune response to SARS-CoV-2 and endemic coronaviruses in urban and indigenous children in Colombia. Fernández Villalobos NV, Marsall P, Torres Páez JC, Strömpl J, Gruber J, Lotto Batista M, Pohl D, Concha G, Frickmann H, de la Hoz Restrepo FP, Schneiderhan-Marra N, Krause G, Dulovic A, Strengert M, Kann S. Commun Med (Lond). 2023; 3 (1)
COVID-19: impact on Public Health and hypothesis-driven investigations on genetic susceptibility and severity.
David S, Dorado G, Duarte EL, David-Bosne S, [...], Rebelo-de-Andrade H.
Immunogenetics. 2022; 74 (4)
DOI: 10.1007/s00251-022-01261-w
COVID-19 is a new complex multisystem disease caused by the novel coronavirus SARS-CoV-2. In slightly over 2 years, it infected nearly 500 million and killed 6 million human beings worldwide, causing an unprecedented coronavirus pandemic. Currently, the international scientific community is engaged in elucidating the molecular mechanisms of the pathophysiology of SARS-CoV-2 infection as a basis of scientific developments for the future control of COVID-19. Global exome and genome analysis efforts work to define the human genetics of protective immunity to SARS-CoV-2 infection. Here, we review the current knowledge regarding the SARS-CoV-2 infection, the implications of COVID-19 to Public Health and discuss genotype to phenotype association approaches that could be exploited through the selection of candidate genes to identify the genetic determinants of severe COVID-19.
2022-03-29 2022 other review-article; Review; Journal Article abstract-available 10.1007/s00251-022-01261-w COVID-19: impact on Public Health and hypothesis-driven investigations on genetic susceptibility and severity. David S, Dorado G, Duarte EL, David-Bosne S, Trigueiro-Louro J, Rebelo-de-Andrade H. Immunogenetics. 2022; 74 (4)
From Cell to Symptoms: The Role of SARS-CoV-2 Cytopathic Effects in the Pathogenesis of COVID-19 and Long COVID.
Gonzalez-Garcia P, Fiorillo Moreno O, Zarate Peñata E, Calderon-Villalba A, [...], Navarro Quiroz E.
Int J Mol Sci. 2023; 24 (9)
DOI: 10.3390/ijms24098290
Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) infection triggers various events from molecular to tissue level, which in turn is given by the intrinsic characteristics of each patient. Given the molecular diversity characteristic of each cellular phenotype, the possible cytopathic, tissue and clinical effects are difficult to predict, which determines the heterogeneity of COVID-19 symptoms. The purpose of this article is to provide a comprehensive review of the cytopathic effects of SARS-CoV-2 on various cell types, focusing on the development of COVID-19, which in turn may lead, in some patients, to a persistence of symptoms after recovery from the disease, a condition known as long COVID. We describe the molecular mechanisms underlying virus-host interactions, including alterations in protein expression, intracellular signaling pathways, and immune responses. In particular, the article highlights the potential impact of these cytopathies on cellular function and clinical outcomes, such as immune dysregulation, neuropsychiatric disorders, and organ damage. The article concludes by discussing future directions for research and implications for the management and treatment of COVID-19 and long COVID.
2023-05-05 2023 other review-article; Review; Journal Article abstract-available 10.3390/ijms24098290 From Cell to Symptoms: The Role of SARS-CoV-2 Cytopathic Effects in the Pathogenesis of COVID-19 and Long COVID. Gonzalez-Garcia P, Fiorillo Moreno O, Zarate Peñata E, Calderon-Villalba A, Pacheco Lugo L, Acosta Hoyos A, Villarreal Camacho JL, Navarro Quiroz R, Pacheco Londoño L, Aroca Martinez G, Moares N, Gabucio A, Fernandez-Ponce C, Garcia-Cozar F, Navarro Quiroz E. Int J Mol Sci. 2023; 24 (9)
Should We Expect an Increase in the Number of Cancer Cases in People with Long COVID?
Amiama-Roig A, Pérez-Martínez L, Rodríguez Ledo P, Verdugo-Sivianes EM, [...], Blanco JR.
Microorganisms. 2023; 11 (3)
DOI: 10.3390/microorganisms11030713
The relationship between viral infections and the risk of developing cancer is well known. Multiple mechanisms participate in and determine this process. The COVID-19 pandemic caused by the SARS-CoV-2 virus has resulted in the deaths of millions of people worldwide. Although the effects of COVID-19 are limited for most people, a large number of people continue to show symptoms for a long period of time (long COVID). Several studies have suggested that cancer could also be a potential long-term complication of the virus; however, the causes of this risk are not yet well understood. In this review, we investigated arguments that could support or reject this possibility.
2023-03-09 2023 other review-article; Review; Journal Article abstract-available 10.3390/microorganisms11030713 Should We Expect an Increase in the Number of Cancer Cases in People with Long COVID? Amiama-Roig A, Pérez-Martínez L, Rodríguez Ledo P, Verdugo-Sivianes EM, Blanco JR. Microorganisms. 2023; 11 (3)
Design, Synthesis and In Vitro Evaluation of Spirooxindole-Based Phenylsulfonyl Moiety as a Candidate Anti-SAR-CoV-2 and MERS-CoV-2 with the Implementation of Combination Studies.
Barakat A, Mostafa A, Ali M, Al-Majid AM, [...], Elshaier YAMM.
Int J Mol Sci. 2022; 23 (19)
DOI: 10.3390/ijms231911861
The search for an effective anti-viral to inhibit COVID-19 is a challenge for the specialized scientific research community. This work investigated the anti-coronavirus activity for spirooxindole-based phenylsulfone cycloadducts in a single and combination protocols. The newly designed anti-SARS-CoV-2 therapeutics spirooxindoles synthesized by [3 + 2] cycloaddition reactions represent an efficient approach. One-pot multicomponent reactions between phenyl vinyl sulfone, substituted isatins, and amines afforded highly stereoselective anti-SARS-CoV-2 therapeutics spirooxindoles with three stereogenic centers. Herein, the newly synthesized spirooxindoles were assessed individually against the highly pathogenic human coronaviruses and proved to be highly potent and safer. Interestingly, the synergistic effect by combining the potent, tested spirooxindoles resulted in an improved antiviral activity as well as better host-cell safety. Compounds 4i and 4d represented the most potent activity against MERS-CoV with IC50 values of 11 and 23 µM, respectively. Both compounds 4c and 4e showed equipotent activity with the best IC50 against SARS-CoV-2 with values of 17 and 18 µM, respectively, then compounds 4d and 4k with IC50 values of 24 and 27 µM, respectively. Then, our attention oriented to perform a combination protocol as anti-SARS-CoV-2 for the best compounds with a different binding mode and accompanied with different pharmacophores. Combination of compound 4k with 4c and combination of compounds 4k with 4i proved to be more active and safer. Compounds 4k with 4i displayed IC50 = 3.275 µM and half maximal cytotoxic-concentration CC50 = 11832 µM. MD simulation of the most potential compounds as well as in silico ADMET properties were investigated. This study highlights the potential drug-like properties of spirooxindoles as a cocktail anti-coronavirus protocol.
2022-10-06 2022 other research-article; Journal Article abstract-available 10.3390/ijms231911861 Design, Synthesis and In Vitro Evaluation of Spirooxindole-Based Phenylsulfonyl Moiety as a Candidate Anti-SAR-CoV-2 and MERS-CoV-2 with the Implementation of Combination Studies. Barakat A, Mostafa A, Ali M, Al-Majid AM, Domingo LR, Kutkat O, Moatasim Y, Zia K, Ul-Haq Z, Elshaier YAMM. Int J Mol Sci. 2022; 23 (19)
Impact of SARS-CoV-2 Infection on the Association Between Laboratory Tests and Severe Outcomes Among Hospitalized Children.
Xie J, Kuppermann N, Florin TA, Tancredi DJ, [...], Freedman SB.
Open Forum Infect Dis. 2023; 10 (10)
DOI: 10.1093/ofid/ofad485

Background

To assist clinicians with identifying children at risk of severe outcomes, we assessed the association between laboratory findings and severe outcomes among severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected children and determined if SARS-CoV-2 test result status modified the associations.

Methods

We conducted a cross-sectional analysis of participants tested for SARS-CoV-2 infection in 41 pediatric emergency departments in 10 countries. Participants were hospitalized, had laboratory testing performed, and completed 14-day follow-up. The primary objective was to assess the associations between laboratory findings and severe outcomes. The secondary objective was to determine if the SARS-CoV-2 test result modified the associations.

Results

We included 1817 participants; 522 (28.7%) SARS-CoV-2 test-positive and 1295 (71.3%) test-negative. Seventy-five (14.4%) test-positive and 174 (13.4%) test-negative children experienced severe outcomes. In regression analysis, we found that among SARS-CoV-2-positive children, procalcitonin ≥0.5 ng/mL (adjusted odds ratio [aOR], 9.14; 95% CI, 2.90-28.80), ferritin >500 ng/mL (aOR, 7.95; 95% CI, 1.89-33.44), D-dimer ≥1500 ng/mL (aOR, 4.57; 95% CI, 1.12-18.68), serum glucose ≥120 mg/dL (aOR, 2.01; 95% CI, 1.06-3.81), lymphocyte count <1.0 × 109/L (aOR, 3.21; 95% CI, 1.34-7.69), and platelet count <150 × 109/L (aOR, 2.82; 95% CI, 1.31-6.07) were associated with severe outcomes. Evaluation of the interaction term revealed that a positive SARS-CoV-2 result increased the associations with severe outcomes for elevated procalcitonin, C-reactive protein (CRP), D-dimer, and for reduced lymphocyte and platelet counts.

Conclusions

Specific laboratory parameters are associated with severe outcomes in SARS-CoV-2-infected children, and elevated serum procalcitonin, CRP, and D-dimer and low absolute lymphocyte and platelet counts were more strongly associated with severe outcomes in children testing positive compared with those testing negative.
2023-10-03 2023 other research-article; Journal Article abstract-available 10.1093/ofid/ofad485 Impact of SARS-CoV-2 Infection on the Association Between Laboratory Tests and Severe Outcomes Among Hospitalized Children. Xie J, Kuppermann N, Florin TA, Tancredi DJ, Funk AL, Kim K, Salvadori MI, Yock-Corrales A, Shah NP, Breslin KA, Chaudhari PP, Bergmann KR, Ahmad FA, Nebhrajani JR, Mintegi S, Gangoiti I, Plint AC, Avva UR, Gardiner MA, Malley R, Finkelstein Y, Dalziel SR, Bhatt M, Kannikeswaran N, Caperell K, Campos C, Sabhaney VJ, Chong SL, Lunoe MM, Rogers AJ, Becker SM, Borland ML, Sartori LF, Pavlicich V, Rino PB, Morrison AK, Neuman MI, Poonai N, Simon NE, Kam AJ, Kwok MY, Morris CR, Palumbo L, Ambroggio L, Navanandan N, Eckerle M, Klassen TP, Payne DC, Cherry JC, Waseem M, Dixon AC, Ferre IB, Freedman SB. Open Forum Infect Dis. 2023; 10 (10)
Performance of amplicon and capture based next-generation sequencing approaches for the epidemiological surveillance of Omicron SARS-CoV-2 and other variants of concern.
Daviña-Núñez C, Pérez S, Cabrera-Alvargonzález JJ, Rincón-Quintero A, [...], Regueiro-García B.
PLoS One. 2024; 19 (4)
DOI: 10.1371/journal.pone.0289188
To control the SARS-CoV-2 pandemic, healthcare systems have focused on ramping up their capacity for epidemiological surveillance through viral whole genome sequencing. In this paper, we tested the performance of two protocols of SARS-CoV-2 nucleic acid enrichment, an amplicon enrichment using different versions of the ARTIC primer panel and a hybrid-capture method using KAPA RNA Hypercap. We focused on the challenge of the Omicron variant sequencing, the advantages of automated library preparation and the influence of the bioinformatic analysis in the final consensus sequence. All 94 samples were sequenced using Illumina iSeq 100 and analysed with two bioinformatic pipelines: a custom-made pipeline and an Illumina-owned pipeline. We were unsuccessful in sequencing six samples using the capture enrichment due to low reads. On the other hand, amplicon dropout and mispriming caused the loss of mutation G21987A and the erroneous addition of mutation T15521A respectively using amplicon enrichment. Overall, we found high sequence agreement regardless of method of enrichment, bioinformatic pipeline or the use of automation for library preparation in eight different SARS-CoV-2 variants. Automation and the use of a simple app for bioinformatic analysis can simplify the genotyping process, making it available for more diagnostic facilities and increasing global vigilance.
2024-04-29 2024 other Research Support, Non-U.S. Gov't; research-article; Journal Article abstract-available 10.1371/journal.pone.0289188 Performance of amplicon and capture based next-generation sequencing approaches for the epidemiological surveillance of Omicron SARS-CoV-2 and other variants of concern. Daviña-Núñez C, Pérez S, Cabrera-Alvargonzález JJ, Rincón-Quintero A, Treinta-Álvarez A, Godoy-Diz M, Suárez-Luque S, Regueiro-García B. PLoS One. 2024; 19 (4)
Utility of bronchoalveolar lavage for COVID-19: a perspective from the Dragon consortium.
Tomassetti S, Ciani L, Luzzi V, Gori L, [...], Guiot J.
Front Med (Lausanne). 2024; 11
DOI: 10.3389/fmed.2024.1259570
Diagnosing COVID-19 and treating its complications remains a challenge. This review reflects the perspective of some of the Dragon (IMI 2-call 21, #101005122) research consortium collaborators on the utility of bronchoalveolar lavage (BAL) in COVID-19. BAL has been proposed as a potentially useful diagnostic tool to increase COVID-19 diagnosis sensitivity. In both critically ill and non-critically ill COVID-19 patients, BAL has a relevant role in detecting other infections or supporting alternative diagnoses and can change management decisions in up to two-thirds of patients. BAL is used to guide steroid and immunosuppressive treatment and to narrow or discontinue antibiotic treatment, reducing the use of unnecessary broad antibiotics. Moreover, cellular analysis and novel multi-omics techniques on BAL are of critical importance for understanding the microenvironment and interaction between epithelial cells and immunity, revealing novel potential prognostic and therapeutic targets. The BAL technique has been described as safe for both patients and healthcare workers in more than a thousand procedures reported to date in the literature. Based on these preliminary studies, we recognize that BAL is a feasible procedure in COVID-19 known or suspected cases, useful to properly guide patient management, and has great potential for research.
2024-02-02 2024 other review-article; Review; Journal Article abstract-available 10.3389/fmed.2024.1259570 Utility of bronchoalveolar lavage for COVID-19: a perspective from the Dragon consortium. Tomassetti S, Ciani L, Luzzi V, Gori L, Trigiani M, Giuntoli L, Lavorini F, Poletti V, Ravaglia C, Torrego A, Maldonado F, Lentz R, Annunziato F, Maggi L, Rossolini GM, Pollini S, Para O, Ciurleo G, Casini A, Rasero L, Bartoloni A, Spinicci M, Munavvar M, Gasparini S, Comin C, Cerinic MM, Peired A, Henket M, Ernst B, Louis R, Corhay JL, Nardi C, Guiot J. Front Med (Lausanne). 2024; 11
Respiratory viruses: their importance and lessons learned from COVID-19.
Cilloniz C, Luna CM, Hurtado JC, Marcos MÁ, [...], Torres A.
Eur Respir Rev. 2022; 31 (166)
DOI: 10.1183/16000617.0051-2022
Respiratory virus infection can cause severe illnesses capable of inducing acute respiratory failure that can progress rapidly to acute respiratory distress syndrome (ARDS). ARDS is related to poor outcomes, especially in individuals with a higher risk of infection, such as the elderly and those with comorbidities, i.e. obesity, asthma, diabetes mellitus and chronic respiratory or cardiovascular disease. Despite this, effective antiviral treatments available for severe viral lung infections are scarce. The coronavirus disease 2019 (COVID-19) pandemic demonstrated that there is also a need to understand the role of airborne transmission of respiratory viruses. Robust evidence supporting this exists, but better comprehension could help implement adequate measures to mitigate respiratory viral infections. In severe viral lung infections, early diagnosis, risk stratification and prognosis are essential in managing patients. Biomarkers can provide reliable, timely and accessible information possibly helpful for clinicians in managing severe lung viral infections. Although respiratory viruses highly impact global health, more research is needed to improve care and prognosis of severe lung viral infections. In this review, we discuss the epidemiology, diagnosis, clinical characteristics, management and prognosis of patients with severe infections due to respiratory viruses.
2022-10-19 2022 other research-article; Review; Journal Article abstract-available 10.1183/16000617.0051-2022 Respiratory viruses: their importance and lessons learned from COVID-19. Cilloniz C, Luna CM, Hurtado JC, Marcos MÁ, Torres A. Eur Respir Rev. 2022; 31 (166)
Electrochemical lateral-flow device for rapid COVID-19 antigen-diagnostic testing.
Deenin W, Yakoh A, Pimpitak U, Pasomsub E, [...], Chaiyo S.
Bioelectrochemistry. 2023; 152
DOI: 10.1016/j.bioelechem.2023.108438
Antigen test kits (ATK) are extensively utilized for screening and diagnosing COVID-19 because they are easy to operate. However, ATKs exhibit poor sensitivity and cannot detect low concentrations of SARS-CoV-2. Herein, we present a new, highly sensitive, and selective device obtained by combining the principle of ATKs with electrochemical detection for COVID-19 diagnosis, which can be quantitatively assessed using a smartphone. An electrochemical test strip (E-test strip) was constructed by attaching a screen-printed electrode inside a lateral-flow device to exploit the remarkable binding affinity of SARS-CoV-2 antigen to ACE2. The ferrocene carboxylic acid attached to SARS-CoV-2 antibody acts as an electroactive species when it binds to SARS-CoV-2 antigen in the sample before it flows continuously to the ACE2-immobilization region on the electrode. Electrochemical-assay signal intensity on smartphones increased proportionally to the concentration of SARS-CoV-2 antigen (LOD = 2.98 pg/mL, under 12 min). Additionally, the application of the single-step E-test strip for COVID-19 screening was demonstrated using nasopharyngeal samples, and the results were consistent with those obtained using the gold standard (RT-PCR). Therefore, the sensor demonstrated excellent performance in assessing and screening COVID-19, and it can be used professionally to accurately verify diagnostic data while remaining rapid, simple, and inexpensive.
2023-04-06 2023 other research-article; Journal Article abstract-available 10.1016/j.bioelechem.2023.108438 Electrochemical lateral-flow device for rapid COVID-19 antigen-diagnostic testing. Deenin W, Yakoh A, Pimpitak U, Pasomsub E, Rengpipat S, Crespo GA, Chaiyo S. Bioelectrochemistry. 2023; 152
Antioxidant and Immune-Related Implications of Minerals in COVID-19: A Possibility for Disease Prevention and Management.
Toledano JM, Puche-Juarez M, Moreno-Fernandez J, Ochoa JJ, [...], Diaz-Castro J.
Antioxidants (Basel). 2023; 12 (5)
DOI: 10.3390/antiox12051104
Since the coronavirus disease 2019 (COVID-19) pandemic appeared, both governments and the scientific community have focused their efforts on the search for prophylactic and therapeutic alternatives in order to reduce its effects. Vaccines against SARS-CoV-2 have been approved and administered, playing a key role in the overcoming of this situation. However, they have not reached the whole world population, and several doses will be needed in the future in order to successfully protect individuals. The disease is still here, so other strategies should be explored with the aim of supporting the immune system before and during the infection. An adequate diet is certainly associated with an optimal inflammatory and oxidative stress status, as poor levels of different nutrients could be related to altered immune responses and, consequently, an augmented susceptibility to infections and severe outcomes derived from them. Minerals exert a wide range of immune-modulatory, anti-inflammatory, antimicrobial, and antioxidant activities, which may be useful for fighting this illness. Although they cannot be considered as a definitive therapeutic solution, the available evidence to date, obtained from studies on similar respiratory diseases, might reflect the rationality of deeper investigations of the use of minerals during this pandemic.
2023-05-16 2023 other review-article; Review; Journal Article abstract-available 10.3390/antiox12051104 Antioxidant and Immune-Related Implications of Minerals in COVID-19: A Possibility for Disease Prevention and Management. Toledano JM, Puche-Juarez M, Moreno-Fernandez J, Ochoa JJ, Diaz-Castro J. Antioxidants (Basel). 2023; 12 (5)
Design and Identification of Inhibitors for the Spike-ACE2 Target of SARS-CoV-2.
Bastos RS, de Lima LR, Neto MFA, Maryam, [...], Santos CBR.
Int J Mol Sci. 2023; 24 (10)
DOI: 10.3390/ijms24108814
When an epidemic started in the Chinese city of Wuhan in December 2019, coronavirus was identified as the cause. Infection by the virus occurs through the interaction of viral S protein with the hosts' angiotensin-converting enzyme 2. By leveraging resources such as the DrugBank database and bioinformatics techniques, ligands with potential activity against the SARS-CoV-2 spike protein were designed and identified in this investigation. The FTMap server and the Molegro software were used to determine the active site of the Spike-ACE2 protein's crystal structure. Virtual screening was performed using a pharmacophore model obtained from antiparasitic drugs, obtaining 2000 molecules from molport®. The ADME/Tox profiles were used to identify the most promising compounds with desirable drug characteristics. The binding affinity investigation was then conducted with selected candidates. A molecular docking study showed five structures with better binding affinity than hydroxychloroquine. Ligand_003 showed a binding affinity of -8.645 kcal·mol-1, which was considered an optimal value for the study. The values presented by ligand_033, ligand_013, ligand_044, and ligand_080 meet the profile of novel drugs. To choose compounds with favorable potential for synthesis, synthetic accessibility studies and similarity analyses were carried out. Molecular dynamics and theoretical IC50 values (ranging from 0.459 to 2.371 µM) demonstrate that these candidates are promising for further tests. Chemical descriptors showed that the candidates had strong molecule stability. Theoretical analyses here show that these molecules have potential as SARS-CoV-2 antivirals and therefore warrant further investigation.
2023-05-16 2023 other research-article; Journal Article abstract-available 10.3390/ijms24108814 Design and Identification of Inhibitors for the Spike-ACE2 Target of SARS-CoV-2. Bastos RS, de Lima LR, Neto MFA, Maryam, Yousaf N, Cruz JN, Campos JM, Kimani NM, Ramos RS, Santos CBR. Int J Mol Sci. 2023; 24 (10)
Zebrafish models of COVID-19.
Tyrkalska SD, Candel S, Pedoto A, García-Moreno D, [...], Mulero V.
FEMS Microbiol Rev. 2023; 47 (1)
DOI: 10.1093/femsre/fuac042
Although COVID-19 has only recently appeared, research studies have already developed and implemented many animal models for deciphering the secrets of the disease and provided insights into the biology of SARS-CoV-2. However, there are several major factors that complicate the study of this virus in model organisms, such as the poor infectivity of clinical isolates of SARS-CoV-2 in some model species, and the absence of persistent infection, immunopathology, severe acute respiratory distress syndrome, and, in general, all the systemic complications which characterize COVID-19 clinically. Another important limitation is that SARS-CoV-2 mainly causes severe COVID-19 in older people with comorbidities, which represents a serious problem when attempting to use young and immunologically naïve laboratory animals in COVID-19 testing. We review here the main animal models developed so far to study COVID-19 and the unique advantages of the zebrafish model that may help to contribute to understand this disease, in particular to the identification and repurposing of drugs to treat COVID-19, to reveal the mechanism of action and side-effects of Spike-based vaccines, and to decipher the high susceptibility of aged people to COVID-19.
2023-01-01 2023 other Research Support, Non-U.S. Gov't; review-article; Review; Journal Article abstract-available 10.1093/femsre/fuac042 Zebrafish models of COVID-19. Tyrkalska SD, Candel S, Pedoto A, García-Moreno D, Alcaraz-Pérez F, Sánchez-Ferrer Á, Cayuela ML, Mulero V. FEMS Microbiol Rev. 2023; 47 (1)
Exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the endangered Iberian lynx (Lynx pardinus).
Gómez JC, Cano-Terriza D, Segalés J, Vergara-Alert J, [...], García-Bocanegra I.
Vet Microbiol. 2024; 290
DOI: 10.1016/j.vetmic.2024.110001
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an emerging zoonotic virus of public and animal health concern, of which felids have been suggested as potential reservoirs. Although SARS-CoV-2 exposure has been detected in domestic and wild captive animals belonging to Felidae family, surveillance has not been carried out in free-ranging wild felids so far. The aim of the present study was to assess SARS-CoV-2 exposure in the Iberian lynx (Lynx pardinus), the most endangered felid in the world. Between 2019 and 2022, we conducted a seroepidemiological study of SARS-CoV-2 in 276 free-ranging and captive Iberian lynxes. Our results evidenced limited (0.4%; 95%CI: 0.0-1.1) but not negligible exposure to this emerging virus in this endangered felid species, increasing the SARS-CoV-2 host range. The circulation of this virus in wildlife evidences the need of integrated European wildlife monitoring.
2024-01-17 2024 other Journal Article abstract-available 10.1016/j.vetmic.2024.110001 Exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the endangered Iberian lynx (Lynx pardinus). Gómez JC, Cano-Terriza D, Segalés J, Vergara-Alert J, Zorrilla I, Del Rey T, Paniagua J, Gonzálvez M, Fernández-Bastit L, Nájera F, Montoya-Oliver JI, Salcedo J, García-Bocanegra I. Vet Microbiol. 2024; 290
Antiviral responses versus virus-induced cellular shutoff: a game of thrones between influenza A virus NS1 and SARS-CoV-2 Nsp1.
Khalil AM, Nogales A, Martínez-Sobrido L, Mostafa A.
Front Cell Infect Microbiol. 2024; 14
DOI: 10.3389/fcimb.2024.1357866
Following virus recognition of host cell receptors and viral particle/genome internalization, viruses replicate in the host via hijacking essential host cell machinery components to evade the provoked antiviral innate immunity against the invading pathogen. Respiratory viral infections are usually acute with the ability to activate pattern recognition receptors (PRRs) in/on host cells, resulting in the production and release of interferons (IFNs), proinflammatory cytokines, chemokines, and IFN-stimulated genes (ISGs) to reduce virus fitness and mitigate infection. Nevertheless, the game between viruses and the host is a complicated and dynamic process, in which they restrict each other via specific factors to maintain their own advantages and win this game. The primary role of the non-structural protein 1 (NS1 and Nsp1) of influenza A viruses (IAV) and the pandemic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), respectively, is to control antiviral host-induced innate immune responses. This review provides a comprehensive overview of the genesis, spatial structure, viral and cellular interactors, and the mechanisms underlying the unique biological functions of IAV NS1 and SARS-CoV-2 Nsp1 in infected host cells. We also highlight the role of both non-structural proteins in modulating viral replication and pathogenicity. Eventually, and because of their important role during viral infection, we also describe their promising potential as targets for antiviral therapy and the development of live attenuated vaccines (LAV). Conclusively, both IAV NS1 and SARS-CoV-2 Nsp1 play an important role in virus-host interactions, viral replication, and pathogenesis, and pave the way to develop novel prophylactic and/or therapeutic interventions for the treatment of these important human respiratory viral pathogens.
2024-02-05 2024 other Research Support, Non-U.S. Gov't; review-article; Review; Journal Article; Research Support, N.I.H., Extramural abstract-available 10.3389/fcimb.2024.1357866 Antiviral responses versus virus-induced cellular shutoff: a game of thrones between influenza A virus NS1 and SARS-CoV-2 Nsp1. Khalil AM, Nogales A, Martínez-Sobrido L, Mostafa A. Front Cell Infect Microbiol. 2024; 14
Genomic determinants of Furin cleavage in diverse European SARS-related bat coronaviruses
Sander A, Moreira-Soto A, Yordanov S, Toplak I, [...], Drexler JF.
bioRxiv; 2021.
DOI: 10.1101/2021.12.15.472779
The furin cleavage site in SARS-CoV-2 is unique within the Severe acute respiratory syndrome–related coronavirus ( SrC ) species. We re-assessed diverse SrC from European horseshoe bats and reveal molecular determinants such as purine richness, RNA secondary structures and viral quasispecies potentially enabling furin cleavage. Furin cleavage thus likely emerged from the SrC bat reservoir via molecular mechanisms conserved across reservoir-bound RNA viruses, supporting a natural origin of SARS-CoV-2.
2021-12-15 2021 other Preprint abstract-available 10.1101/2021.12.15.472779 Genomic determinants of Furin cleavage in diverse European SARS-related bat coronaviruses Sander A, Moreira-Soto A, Yordanov S, Toplak I, Balboni A, Ameneiros RS, Corman V, Drosten C, Drexler JF. bioRxiv; 2021.
Cell-mediated and Neutralizing Antibody Responses to the SARS-CoV-2 Omicron BA.4/BA.5-adapted Bivalent Vaccine Booster in Kidney and Liver Transplant Recipients.
Fernández-Ruiz M, Almendro-Vázquez P, Redondo N, Ruiz-Merlo T, [...], Aguado JM.
Transplant Direct. 2023; 9 (10)
DOI: 10.1097/txd.0000000000001536

Background

The immunogenicity elicited by the Omicron BA.4/BA.5-adapted bivalent booster vaccine after solid organ transplantation (SOT) has not been characterized.

Methods

We assessed cell-mediated and neutralizing IgG antibody responses against the BA.4/BA.5 spike receptor-binding domain at baseline and 2 wk after the administration of an mRNA-based bivalent (ancestral strain and BA.4/BA.5 subvariants) vaccine among 30 SOT recipients who had received ≥3 monovalent vaccine doses. Previous coronavirus disease 2019 history was present in 46.7% of them. We also recruited a control group of 19 nontransplant healthy individuals. Cell-mediated immunity was measured by fluorescent ELISpot assay for interferon (IFN)-γ secretion, whereas the neutralizing IgG antibody response against the BA.4/BA.5 spike receptor-binding domain was quantified with a competitive ELISA.

Results

The median number of BA.4/BA.5 spike-specific IFN-γ-producing spot-forming units (SFUs) increased from baseline to 2 wk postbooster (83.8 versus 133.0 SFUs/106 peripheral blood mononuclear cells; P = 0.0017). Seropositivity rate also increased (46.7%-83.3%; P = 0.001), as well as serum neutralizing activity (4.2%-78.3%; P < 0.0001). Patients with no prior coronavirus disease 2019 history experienced higher improvements in cell-mediated and neutralizing responses after booster vaccination. There was no correlation between BA.4/BA.5 spike-specific IFN-γ-producing SFUs and neutralizing activity. Nontransplant controls showed more robust postbooster cell-mediated immunity than SOT recipients (591.1 versus 133.0 IFN-γ-producing SFUs/106 peripheral blood mononuclear cells; P < 0.0001), although no differences were observed for antibody responses in terms of postbooster seropositivity rates or neutralizing activity.

Conclusions

Booster with the BA.4/BA.5-adapted bivalent vaccine generated strong subvariant-specific responses among SOT recipients. Booster-induced cell-mediated immunity, however, remained lower than in immunocompetent individuals.
2023-09-20 2023 other research-article; Journal Article abstract-available 10.1097/txd.0000000000001536 Cell-mediated and Neutralizing Antibody Responses to the SARS-CoV-2 Omicron BA.4/BA.5-adapted Bivalent Vaccine Booster in Kidney and Liver Transplant Recipients. Fernández-Ruiz M, Almendro-Vázquez P, Redondo N, Ruiz-Merlo T, Abella S, Somoza A, López-Medrano F, San Juan R, Loinaz C, Andrés A, Paz-Artal E, Aguado JM. Transplant Direct. 2023; 9 (10)
Genetic Association between ACE2 (rs2285666 and rs2074192) and TMPRSS2 (rs12329760 and rs2070788) Polymorphisms with Post-COVID Symptoms in Previously Hospitalized COVID-19 Survivors.
Fernández-de-Las-Peñas C, Arendt-Nielsen L, Díaz-Gil G, Gómez-Esquer F, [...], Giordano R.
Genes (Basel). 2022; 13 (11)
DOI: 10.3390/genes13111935
The aim of the study was to identify the association between four selected COVID-19 polymorphisms of ACE2 and TMPRSS2 receptors genes with the presence of long-COVID symptomatology in COVID-19 survivors. These genes were selected as they associate with the entry of the SARS-CoV-2 virus into the cells, so polymorphisms could be important for the prognoses of long-COVID symptoms. Two hundred and ninety-three (n = 293, 49.5% female, mean age: 55.6 ± 12.9 years) individuals who had been previously hospitalized due to COVID-19 were included. Three potential genotypes of the following single nucleotide polymorphisms (SNPs) were obtained from non-stimulated saliva samples of participants: ACE2 (rs2285666), ACE2 (rs2074192), TMPRSS2 (rs12329760), TMPRSS2 (rs2070788). Participants were asked to self-report the presence of any post-COVID defined as a symptom that started no later than one month after SARS-CoV-2 acute infection and whether the symptom persisted at the time of the study. At the time of the study (mean: 17.8, SD: 5.2 months after hospital discharge), 87.7% patients reported at least one symptom. Fatigue (62.8%), pain (39.9%) or memory loss (32.1%) were the most prevalent post-COVID symptoms. Overall, no differences in long-COVID symptoms were dependent on ACE2 rs2285666, ACE2 rs2074192, TMPRSS2 rs12329760, or TMPRSS2 rs2070788 genotypes. The four SNPs assessed, albeit previously associated with COVID-19 severity, do not predispose for developing long-COVID symptoms in people who were previously hospitalized due to COVID-19 during the first wave of the pandemic.
2022-10-24 2022 other Research Support, Non-U.S. Gov't; research-article; Journal Article abstract-available 10.3390/genes13111935 Genetic Association between ACE2 (rs2285666 and rs2074192) and TMPRSS2 (rs12329760 and rs2070788) Polymorphisms with Post-COVID Symptoms in Previously Hospitalized COVID-19 Survivors. Fernández-de-Las-Peñas C, Arendt-Nielsen L, Díaz-Gil G, Gómez-Esquer F, Gil-Crujera A, Gómez-Sánchez SM, Ambite-Quesada S, Palomar-Gallego MA, Pellicer-Valero OJ, Giordano R. Genes (Basel). 2022; 13 (11)
No Remdesivir Resistance Observed in the Phase 3 Severe and Moderate COVID-19 SIMPLE Trials.
Hedskog C, Spinner CD, Protzer U, Hoffmann D, [...], Porter DP.
Viruses. 2024; 16 (4)
DOI: 10.3390/v16040546
Remdesivir (RDV) is a broad-spectrum nucleotide analog prodrug approved for the treatment of COVID-19 in hospitalized and non-hospitalized patients with clinical benefit demonstrated in multiple Phase 3 trials. Here we present SARS-CoV-2 resistance analyses from the Phase 3 SIMPLE clinical studies evaluating RDV in hospitalized participants with severe or moderate COVID-19 disease. The severe and moderate studies enrolled participants with radiologic evidence of pneumonia and a room-air oxygen saturation of ≤94% or >94%, respectively. Virology sample collection was optional in the study protocols. Sequencing and related viral load data were obtained retrospectively from participants at a subset of study sites with local sequencing capabilities (10 of 183 sites) at timepoints with detectable viral load. Among participants with both baseline and post-baseline sequencing data treated with RDV, emergent Nsp12 substitutions were observed in 4 of 19 (21%) participants in the severe study and none of the 2 participants in the moderate study. The following 5 substitutions emerged: T76I, A526V, A554V, E665K, and C697F. The substitutions T76I, A526V, A554V, and C697F had an EC50 fold change of ≤1.5 relative to the wildtype reference using a SARS-CoV-2 subgenomic replicon system, indicating no significant change in the susceptibility to RDV. The phenotyping of E665K could not be determined due to a lack of replication. These data reveal no evidence of relevant resistance emergence and further confirm the established efficacy profile of RDV with a high resistance barrier in COVID-19 patients.
2024-03-31 2024 other Clinical Trial, Phase III; Research Support, Non-U.S. Gov't; research-article; Journal Article abstract-available 10.3390/v16040546 No Remdesivir Resistance Observed in the Phase 3 Severe and Moderate COVID-19 SIMPLE Trials. Hedskog C, Spinner CD, Protzer U, Hoffmann D, Ko C, Gottlieb RL, Askar M, Roestenberg M, de Vries JJC, Carbo EC, Martin R, Li J, Han D, Rodriguez L, Parvangada A, Perry JK, Ferrer R, Antón A, Andrés C, Casares V, Günthard HF, Huber M, McComsey GA, Sadri N, Aberg JA, van Bakel H, Porter DP. Viruses. 2024; 16 (4)
Disparities in Coronavirus Disease 2019 Clinical Outcomes and Vaccination Coverage Among Migrants With Human Immunodeficiency Virus in the PISCIS Cohort: A Population-Based Propensity Score-Matched Analysis.
Nomah DK, Díaz Y, Bruguera A, Moreno-Fornés S, [...], Miró JM.
Open Forum Infect Dis. 2024; 11 (1)
DOI: 10.1093/ofid/ofad693

Background

Coronavirus disease 2019 (COVID-19) disproportionately affects migrants and ethnic minorities, including those with human immunodeficiency virus (HIV). Comprehensive studies are needed to understand the impact and risk factors.

Methods

Using data from the PISCIS cohort of people with HIV (PWH) in Catalonia, Spain, we investigated COVID-19 outcomes and vaccination coverage. Among 10 640 PWH we compared migrants and non-migrants assessing rates of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing, diagnosis, and associated clinical outcomes through propensity score matching and multivariable Cox regression.

Results

The cohort (mean age, 43 years; 83.5% male) included 57.4% (3053) Latin American migrants. Migrants with HIV (MWH) had fewer SARS-CoV-2 tests (67.8% vs 72.1%, P < .0001) but similar COVID-19 diagnoses (29.2% vs 29.4%, P = .847) compared to Spanish natives. Migrants had lower complete vaccination (78.9% vs 85.1%, P < .0001) and booster doses (63.0% vs 65.5%, P = .027). COVID-19 hospitalizations (8.1% vs 5.1%, P < .0001) and intensive care unit (ICU) admissions (2.9% vs 1.2%, P < .0001) were higher among migrants, with similar hospitalization duration (5.5 vs 4.0 days, P = .098) and mortality (3 [0.2%] vs 6 [0.4%], P = .510). Age ≥40 years, CD4 counts <200 cells/μL, ≥2 comorbidities, and incomplete/nonreception of the SARS-CoV-2 vaccine increased the risk of severe COVID-19 among migrants.

Conclusions

MWH had lower rates of SARS-CoV-2 testing and vaccination coverage, although the rates of COVID-19 diagnosis were similar between migrants and non-migrants. Rates of COVID-19-associated hospitalizations and ICU admissions were higher among migrants in comparison with non-migrants, with similar hospitalization duration and mortality. These findings can inform policies to address disparities in future pandemic responses for MWH.
2024-01-05 2024 other research-article; Journal Article abstract-available 10.1093/ofid/ofad693 Disparities in Coronavirus Disease 2019 Clinical Outcomes and Vaccination Coverage Among Migrants With Human Immunodeficiency Virus in the PISCIS Cohort: A Population-Based Propensity Score-Matched Analysis. Nomah DK, Díaz Y, Bruguera A, Moreno-Fornés S, Aceiton J, Reyes-Urueña J, Llibre JM, Falcó V, Imaz A, Fanjul FJ, Peraire J, Deig E, Domingo P, Inciarte A, Casabona J, Miró JM. Open Forum Infect Dis. 2024; 11 (1)
Measurement of IFN-γ and IL-2 for the assessment of the cellular immunity against SARS-CoV-2.
Safont G, Villar-Hernández R, Smalchuk D, Stojanovic Z, [...], Domínguez J.
Sci Rep. 2024; 14 (1)
DOI: 10.1038/s41598-024-51505-w
The study of specific T-cell responses against SARS-CoV-2 is important for understanding long-term immunity and infection management. The aim of this study was to assess the dual IFN-γ and IL-2 detection, using a SARS-CoV-2 specific fluorescence ELISPOT, in patients undergoing acute disease, during convalescence, and after vaccination. We also evaluated humoral response and compared with T-cells with the aim of correlating both types of responses, and increase the number of specific response detection. Blood samples were drawn from acute COVID-19 patients and convalescent individuals classified according to disease severity; and from unvaccinated and vaccinated uninfected individuals. IgGs against Spike and nucleocapsid, IgMs against nucleocapsid, and neutralizing antibodies were also analyzed. Our results show that IFN-γ in combination with IL-2 increases response detection in acute and convalescent individuals (p = 0.023). In addition, IFN-γ detection can be a useful biomarker for monitoring severe acute patients, as our results indicate that those individuals with a poor outcome have lower levels of this cytokine. In some cases, the lack of cellular immunity is compensated by antibodies, confirming the role of both types of immune responses in infection, and confirming that their dual detection can increase the number of specific response detections. In summary, IFN-γ/IL-2 dual detection is promising for characterizing and assessing the immunization status, and helping in the patient management.
2024-01-11 2024 other research-article; Journal Article abstract-available 10.1038/s41598-024-51505-w Measurement of IFN-γ and IL-2 for the assessment of the cellular immunity against SARS-CoV-2. Safont G, Villar-Hernández R, Smalchuk D, Stojanovic Z, Marín A, Lacoma A, Pérez-Cano C, López-Martínez A, Molina-Moya B, Solis AJ, Arméstar F, Matllo J, Díaz-Fernández S, Romero I, Casas I, Strecker K, Preyer R, Rosell A, Latorre I, Domínguez J. Sci Rep. 2024; 14 (1)
Optimized vaccine candidate MVA-S(3P) fully protects against SARS-CoV-2 infection in hamsters.
Abdelnabi R, Pérez P, Astorgano D, Albericio G, [...], García-Arriaza J.
Front Immunol. 2023; 14
DOI: 10.3389/fimmu.2023.1163159
The development of novel optimized vaccines against coronavirus disease 2019 (COVID-19) that are capable of controlling the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic and the appearance of different variants of concern (VoC) is needed to fully prevent the transmission of the virus. In the present study, we describe the enhanced immunogenicity and efficacy elicited in hamsters by a modified vaccinia virus Ankara (MVA) vector expressing a full-length prefusion-stabilized SARS-CoV-2 spike (S) protein [termed MVA-S(3P)]. Hamsters vaccinated with one or two doses of MVA-S(3P) developed high titers of S-binding IgG antibodies and neutralizing antibodies against the ancestral Wuhan SARS-CoV-2 virus and VoC beta, gamma, and delta, as well as against omicron, although with a somewhat lower neutralization activity. After SARS-CoV-2 challenge, vaccinated hamsters did not lose body weight as compared to matched placebo (MVA-WT) controls. Consistently, vaccinated hamsters exhibited significantly reduced viral RNA in the lungs and nasal washes, and no infectious virus was detected in the lungs in comparison to controls. Furthermore, almost no lung histopathology was detected in MVA-S(3P)-vaccinated hamsters, which also showed significantly reduced levels of proinflammatory cytokines in the lungs compared to unvaccinated hamsters. These results reinforce the use of MVA-S(3P) as a vaccine candidate against COVID-19 in clinical trials.
2023-10-18 2023 other Research Support, Non-U.S. Gov't; research-article; Journal Article abstract-available 10.3389/fimmu.2023.1163159 Optimized vaccine candidate MVA-S(3P) fully protects against SARS-CoV-2 infection in hamsters. Abdelnabi R, Pérez P, Astorgano D, Albericio G, Kerstens W, Thibaut HJ, Coelmont L, Weynand B, Labiod N, Delgado R, Montenegro D, Puentes E, Rodríguez E, Neyts J, Dallmeier K, Esteban M, García-Arriaza J. Front Immunol. 2023; 14
Effectiveness of Adapted COVID-19 Vaccines and Ability to Establish Herd Immunity against Omicron BA.1 and BA4-5 Variants of SARS-CoV-2.
Plans-Rubió P.
Vaccines (Basel). 2023; 11 (12)
DOI: 10.3390/vaccines11121836
The emergence of novel SARS-CoV-2 variants has raised concerns about the ability of COVID-19 vaccination programs to establish adequate herd immunity levels in the population. This study assessed the effectiveness of adapted vaccines in preventing SARS-CoV-2 infection and the ability of the adapted vaccines to establish herd immunity against emerging Omicron variants. A systematic literature review was conducted to estimate the absolute vaccine effectiveness (aVE) in preventing SARS-CoV-2 infection using adapted vaccines targeting Omicron variants. The ability of the adapted vaccines to establish herd immunity was assessed by taking into account the following factors: aVE, Ro values of SARS-CoV-2 and the use of non-pharmacological interventions (NPIs). This study found meta-analysis-based aVEs in preventing severe disease and SARS-CoV-2 infection of 56-60% and 36-39%, respectively. Adapted vaccines could not establish herd immunity against the Omicron BA.1 and BA.4-5 variants without using non-pharmacological interventions (NPIs). The adapted vaccines could establish herd immunity only by achieving >80% vaccination coverage, using NPIs with greater effectiveness and when 20-30% of individuals were already protected against SARS-CoV-2 in the population. New adapted COVID-19 vaccines with greater effectiveness in preventing SARS-CoV-2 infection must be developed to increase herd immunity levels against emerging SARS-CoV-2 variants in the population.
2023-12-10 2023 other research-article; Journal Article abstract-available 10.3390/vaccines11121836 Effectiveness of Adapted COVID-19 Vaccines and Ability to Establish Herd Immunity against Omicron BA.1 and BA4-5 Variants of SARS-CoV-2. Plans-Rubió P. Vaccines (Basel). 2023; 11 (12)
Aetiological and prognostic roles of frailty, multimorbidity and socioeconomic characteristics in the development of SARS-CoV-2 health outcomes: protocol for systematic reviews of population-based studies.
Makovski TT, Ghattas J, Monnier Besnard S, Ambrozova M, [...], Carcaillon-Bentata L.
BMJ Open. 2022; 12 (11)
DOI: 10.1136/bmjopen-2022-063573

Introduction

There is growing evidence that the impact of COVID-19 crisis may be stronger for individuals with multimorbidity, frailty and lower socioeconomic status. Existing reviews focus on few, mainly short-term effects of COVID-19 illness and patients with single chronic disease. Information is also largely missing for population representative samples.Applying population-based approach, the systematic reviews will have two objectives: (1) to evaluate the aetiological roles of frailty, multimorbidity and socioeconomic status on SARS-CoV-2 infection probability, hospitalisation, intensive care unit (ICU) admission, mechanical ventilation and COVID-19 related mortality among general population and (2) to investigate the prognostic roles of frailty, multimorbidity and socioeconomic characteristics on the risk of hospitalisation, ICU admission, mechanical ventilation, COVID-19 mortality, functioning, quality of life, disability, mental health and work absence.

Methods and analysis

For this ongoing work, four databases were searched: PubMed, Embase, WHO COVID-19 Global literature on coronavirus disease and PsycINFO, for the period between January 2020 and April 7 2021. Peer-reviewed published literature in English and all types of population-based studies will be considered. Studies using standard tools to assess multimorbidity such as disease count, comorbidity indices or disease combinations will be retained, as well as studies with standard scales and scores for frailty or measurement of a socioeconomic gradient. Initial search included 10 139 articles, 411 for full-text reading. Results will be summarised by risk factor, objective and outcome. The feasibility of meta-analysis will be determined by the findings and will aim to better understand uncertainties of the results. Quality of studies will be assessed using standardised scales.

Ethics and dissemination

The study will be based on published evidence, and it is exempt from the ethical approval. This work is part of the Population Health Information Research Infrastructure (PHIRI) project. Dissemination of the results will imply conference presentation, submission for scientific publication and PHIRI project report.

Prospero registration number

CRD42021249444.
2022-11-22 2022 other Research Support, Non-U.S. Gov't; systematic-review; Journal Article abstract-available 10.1136/bmjopen-2022-063573 Aetiological and prognostic roles of frailty, multimorbidity and socioeconomic characteristics in the development of SARS-CoV-2 health outcomes: protocol for systematic reviews of population-based studies. Makovski TT, Ghattas J, Monnier Besnard S, Ambrozova M, Vasinova B, Feteira-Santos R, Bezzegh P, Ponce Bollmann F, Cottam J, Haneef R, Devleesschauwer B, Speybroeck N, Nogueira P, Forjaz MJ, Coste J, Carcaillon-Bentata L. BMJ Open. 2022; 12 (11)
Conserved structures and dynamics in 5'-proximal regions of Betacoronavirus RNA genomes.
de Moura TR, Purta E, Bernat A, Martín-Cuevas EM, [...], Bujnicki JM.
Nucleic Acids Res. 2024; 52 (6)
DOI: 10.1093/nar/gkae144
Betacoronaviruses are a genus within the Coronaviridae family of RNA viruses. They are capable of infecting vertebrates and causing epidemics as well as global pandemics in humans. Mitigating the threat posed by Betacoronaviruses requires an understanding of their molecular diversity. The development of novel antivirals hinges on understanding the key regulatory elements within the viral RNA genomes, in particular the 5'-proximal region, which is pivotal for viral protein synthesis. Using a combination of cryo-electron microscopy, atomic force microscopy, chemical probing, and computational modeling, we determined the structures of 5'-proximal regions in RNA genomes of Betacoronaviruses from four subgenera: OC43-CoV, SARS-CoV-2, MERS-CoV, and Rousettus bat-CoV. We obtained cryo-electron microscopy maps and determined atomic-resolution models for the stem-loop-5 (SL5) region at the translation start site and found that despite low sequence similarity and variable length of the helical elements it exhibits a remarkable structural conservation. Atomic force microscopy imaging revealed a common domain organization and a dynamic arrangement of structural elements connected with flexible linkers across all four Betacoronavirus subgenera. Together, these results reveal common features of a critical regulatory region shared between different Betacoronavirus RNA genomes, which may allow targeting of these RNAs by broad-spectrum antiviral therapeutics.
2024-04-01 2024 other research-article; Journal Article abstract-available 10.1093/nar/gkae144 Conserved structures and dynamics in 5'-proximal regions of Betacoronavirus RNA genomes. de Moura TR, Purta E, Bernat A, Martín-Cuevas EM, Kurkowska M, Baulin EF, Mukherjee S, Nowak J, Biela AP, Rawski M, Glatt S, Moreno-Herrero F, Bujnicki JM. Nucleic Acids Res. 2024; 52 (6)
Maternal COVID-19 Serological Changes-Comparison between Seroconversion Rate in First and Third Trimesters of Pregnancy and Subsequent Obstetric Complications: A Cohort Study.
Rayo MN, Aquise A, Fernandez-Buhigas I, Gonzalez-Gea L, [...], Gil MM.
Viruses. 2023; 15 (12)
DOI: 10.3390/v15122386
Pregnant women are especially vulnerable to respiratory diseases. We aimed to study seroconversion rates during pregnancy in a cohort of consecutive pregnancies tested in the first and third trimesters and to compare the maternal and obstetric complications in the women who seroconverted in the first trimester and those who did so in the third. This was an observational cohort study carried out at the Hospital Universitario de Torrejón, in Madrid, Spain, during the first peak of the COVID-19 pandemic. All consecutive singleton pregnancies with a viable fetus attending their 11-13-week scan between 1 January and 15 May 2020 were included and seropositive women for SARS-CoV2 were monthly follow up until delivery. Antibodies against SARS-CoV-2 (IgA and IgG) were analyzed on stored serum samples obtained from first- and third-trimester routine antenatal bloods in 470 pregnant women. Antibodies against SARS-CoV-2 were detected in 31 (6.6%) women in the first trimester and in 66 (14.0%) in the third trimester, including 48 (10.2%) that were negative in the first trimester (seroconversion during pregnancy). Although the rate of infection was significantly higher in the third versus the first trimester (p = 0.003), no significant differences in maternal or obstetric complications were observed in women testing positive in the first versus the third trimester.
2023-12-05 2023 other research-article; Journal Article; Observational Study abstract-available 10.3390/v15122386 Maternal COVID-19 Serological Changes-Comparison between Seroconversion Rate in First and Third Trimesters of Pregnancy and Subsequent Obstetric Complications: A Cohort Study. Rayo MN, Aquise A, Fernandez-Buhigas I, Gonzalez-Gea L, Garcia-Gonzalez C, Sanchez-Tudela M, Rodriguez-Fernandez M, Tuñon-Le Poultel D, Santacruz B, Gil MM. Viruses. 2023; 15 (12)
Nonspecific Effects of Infant Vaccines Make Children More Resistant to SARS-CoV-2 Infection.
Fonte L, Ginori M, García G, Hernández Y, [...], Calderón EJ.
Children (Basel). 2022; 9 (12)
DOI: 10.3390/children9121858
A myriad of reasons, or a combination of them, have been alluded to in order to explain the lower susceptibility of children to SARS-CoV-2 infection and the development of severe forms of COVID-19. This document explores an additional factor, still little addressed in the medical literature related to the matter: nonspecific resistance to SARS-CoV-2 that could be generated by vaccines administered during childhood. The analysis carried out allows one to conclude that a group of vaccines administered during childhood is associated with a lower incidence and severity of SARS-CoV-2 infection among pediatric ages. Looking from an epidemiological perspective, this conclusion must be taken into consideration in order to ensure greater rationality in the design and implementation of prevention and control actions, including the administration of the COVID-19 vaccine, for these ages.
2022-11-29 2022 other other; Journal Article abstract-available 10.3390/children9121858 Nonspecific Effects of Infant Vaccines Make Children More Resistant to <i>SARS-CoV-2</i> Infection. Fonte L, Ginori M, García G, Hernández Y, de Armas Y, Calderón EJ. Children (Basel). 2022; 9 (12)
Immunoglobulins in COVID-19 pneumonia: from the acute phase to the recovery phase.
Peraire J, García-Pardo G, Chafino S, Sánchez A, [...], Rull A.
Eur J Med Res. 2024; 29 (1)
DOI: 10.1186/s40001-024-01824-5

Background

COVID-19 pneumonia causes hyperinflammatory response that culminates in acute respiratory syndrome (ARDS) related to increased multiorgan dysfunction and mortality risk. Antiviral-neutralizing immunoglobulins production reflect the host humoral status and illness severity, and thus, immunoglobulin (Ig) circulating levels could be evidence of COVID-19 prognosis.

Methods

The relationship among circulating immunoglobulins (IgA, IgG, IgM) and COVID-19 pneumonia was evaluated using clinical information and blood samples in a COVID-19 cohort composed by 320 individuals recruited during the acute phase and followed up to 4 to 8 weeks (n = 252) from the Spanish first to fourth waves.

Results

COVID-19 pneumonia development depended on baseline Ig concentrations. Circulating IgA levels together with clinical features at acute phase was highly associated with COVID-19 pneumonia development. IgM was positively correlated with obesity (ρb = 0.156, P = 0.020), dyslipemia (ρb = 0.140, P = 0.029), COPD (ρb = 0.133, P = 0.037), cancer (ρb = 0.173, P = 0.007) and hypertension (ρb = 0.148, P = 0.020). Ig concentrations at recovery phase were related to COVID-19 treatments.

Conclusions

Our results provide valuable information on the dynamics of immunoglobulins upon SARS-CoV-2 infection or other similar viruses.
2024-04-06 2024 other research-article; Journal Article abstract-available 10.1186/s40001-024-01824-5 Immunoglobulins in COVID-19 pneumonia: from the acute phase to the recovery phase. Peraire J, García-Pardo G, Chafino S, Sánchez A, Botero-Gallego M, Olona M, Espineira S, Reverté L, Skouridou V, Peiró ÓM, Gómez-Bertomeu F, Vidal F, O' Sullivan CK, Rull A. Eur J Med Res. 2024; 29 (1)
The dynamics of neutralizing antibodies against SARS-CoV-2 in cats naturally exposed to virus reveals an increase in antibody activity after re-infection.
Villanueva-Saz S, Martínez M, Rueda P, Bolea S, [...], Arias M.
Vet Res Commun. 2023; 47 (4)
DOI: 10.1007/s11259-023-10087-0
Severe Acute Respiratory Syndrome Coronavirus 2 is the causative agent of Coronavirus Disease 2019 in humans. To date, little is known about the persistence of antibodies against SARS-CoV-2 in animals under natural conditions, in particular susceptible pets such as cat. This study reports the detection and monitoring of the humoral response against SARS-CoV-2 including the detection of immunoglobulins G specific for receptor binding domain of SARS-CoV-2 spike protein by an enzyme-linked immunosorbent assay and neutralizing antibodies by virus neutralization assay. Results showed that these antibodies last longer than 16 months in two naturally apparently healthy infected cats with the absence of clinicopathological findings during the follow-up. Moreover, re-infection is also possible with an important increase in virus neutralization test titers in both animals with no evident systemic signs found during each physical examination and with values of hematologic and biochemical parameters inside the normal reference intervals. Our results confirm a slow but progressive decrease of the kinetics and immunity of neutralizing antibodies in cats after the infection. Furthermore, similar to humans SARS-CoV-2 reinfection can stimulate an increase of the neutralizing antibodies determined by these two serological techniques in domestic cats.
2023-03-15 2023 other research-article; Journal Article abstract-available 10.1007/s11259-023-10087-0 The dynamics of neutralizing antibodies against SARS-CoV-2 in cats naturally exposed to virus reveals an increase in antibody activity after re-infection. Villanueva-Saz S, Martínez M, Rueda P, Bolea S, Pérez MD, Verde M, Yzuel A, Hurtado-Guerrero R, Pardo J, Santiago L, Fernández A, Arias M. Vet Res Commun. 2023; 47 (4)
Calcium Signaling Pathway Is Involved in the Shedding of ACE2 Catalytic Ectodomain: New Insights for Clinical and Therapeutic Applications of ACE2 for COVID-19.
García-Escobar A, Vera-Vera S, Jurado-Román A, Jiménez-Valero S, [...], Moreno R.
Biomolecules. 2022; 12 (1)
DOI: 10.3390/biom12010076
The angiotensin-converting enzyme 2 (ACE2) is a type I integral membrane that exists in two forms: the first is a transmembrane protein; the second is a soluble catalytic ectodomain of ACE2. The catalytic ectodomain of ACE2 undergoes shedding by a disintegrin and metalloproteinase domain-containing protein 17 (ADAM17), in which calmodulin mediates the calcium signaling pathway that is involved in ACE2 release, resulting in a soluble catalytic ectodomain of ACE2 that can be measured as soluble ACE2 plasma activity. The shedding of the ACE2 catalytic ectodomain plays a role in cardiac remodeling and endothelial dysfunction and is a predictor of all-cause mortality, including cardiovascular mortality. Moreover, considerable evidence supports that the ACE2 catalytic ectodomain is an essential entry receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Additionally, endotoxins and the pro-inflammatory cytokines interleukin (IL)-1β and tumor necrosis factor-alpha (TNFα) all enhanced soluble catalytic ectodomain ACE2 shedding from the airway epithelia, suggesting that the shedding of ACE2 may represent a mechanism by which viral entry and infection may be controlled such as some types of betacoronavirus. In this regard, ACE2 plays an important role in inflammation and thrombotic response, and its down-regulation may aggravate COVID-19 via the renin-angiotensin system, including by promoting pathological changes in lung injury. Soluble forms of ACE2 have recently been shown to inhibit SARS-CoV-2 infection. Furthermore, given that vitamin D enhanced the shedding of ACE2, some studies reported that vitamin D treatment is associated with prognosis improvement in COVID-19. This is an updated review on the evidence, clinical, and therapeutic applications of ACE2 for COVID-19.
2022-01-05 2022 other review-article; Review; Journal Article abstract-available 10.3390/biom12010076 Calcium Signaling Pathway Is Involved in the Shedding of ACE2 Catalytic Ectodomain: New Insights for Clinical and Therapeutic Applications of ACE2 for COVID-19. García-Escobar A, Vera-Vera S, Jurado-Román A, Jiménez-Valero S, Galeote G, Moreno R. Biomolecules. 2022; 12 (1)
COVID-19: A Comprehensive Review on Cardiovascular Alterations, Immunity, and Therapeutics in Older Adults.
Rivera-Torres J, Girón N, San José E.
J Clin Med. 2023; 12 (2)
DOI: 10.3390/jcm12020488
Here, we present a review focusing on three relevant issues related to COVID-19 and its impact in older adults (60 years and older). SARS-CoV-2 infection starts in the respiratory system, but the development of systemic diseases accompanied by severe clinical manifestations has also been reported, with cardiovascular and immune system dysfunction being the major ones. Additionally, the presence of comorbidities and aging represent major risk factors for the severity and poor prognosis of the disease. Since aging-associated decline has been largely related to immune and cardiovascular alterations, we sought to investigate the consequences and the underlying mechanisms of these pathologies to understand the severity of the illness in this population. Understanding the effects of COVID-19 on both systems should translate into comprehensive and improved medical care for elderly COVID-19 patients, preventing cardiovascular as well as immunological alterations in this population. Approved therapies that contribute to the improvement of symptoms and a reduction in mortality, as well as new therapies in development, constitute an approach to managing these disorders. Among them, we describe antivirals, cytokine antagonists, cytokine signaling pathway inhibitors, and vaccines.
2023-01-06 2023 other review-article; Review; Journal Article abstract-available 10.3390/jcm12020488 COVID-19: A Comprehensive Review on Cardiovascular Alterations, Immunity, and Therapeutics in Older Adults. Rivera-Torres J, Girón N, San José E. J Clin Med. 2023; 12 (2)
mRNA Vaccines against SARS-CoV-2: Advantages and Caveats.
Echaide M, Chocarro de Erauso L, Bocanegra A, Blanco E, [...], Escors D.
Int J Mol Sci. 2023; 24 (6)
DOI: 10.3390/ijms24065944
The application of BNT162b2 and mRNA-1273 vaccines against SARS-CoV-2 infection has constituted a determinant resource to control the COVID-19 pandemic. Since the beginning of 2021, millions of doses have been administered in several countries of North and South America and Europe. Many studies have confirmed the efficacy of these vaccines in a wide range of ages and in vulnerable groups of people against COVID-19. Nevertheless, the emergence and selection of new variants have led to a progressive decay in vaccine efficacy. Pfizer-BioNTech and Moderna developed updated bivalent vaccines-Comirnaty and Spikevax-to improve responses against the SARS-CoV-2 Omicron variants. Frequent booster doses with monovalent or bivalent mRNA vaccines, the emergence of some rare but serious adverse events and the activation of T-helper 17 responses suggest the need for improved mRNA vaccine formulations or the use of other types of vaccines. In this review, we discuss the advantages and limitations of mRNA vaccines targeting SARS-CoV-2 focusing on the most recent, related publications.
2023-03-21 2023 fondo-covid review-article; Review; Journal Article abstract-available 10.3390/ijms24065944 mRNA Vaccines against SARS-CoV-2: Advantages and Caveats. Echaide M, Chocarro de Erauso L, Bocanegra A, Blanco E, Kochan G, Escors D. Int J Mol Sci. 2023; 24 (6)
COVID-19 vaccine effectiveness against symptomatic infection with SARS-CoV-2 BA.1/BA.2 lineages among adults and adolescents in a multicentre primary care study, Europe, December 2021 to June 2022.
Lanièce Delaunay C, Martínez-Baz I, Sève N, Domegan L, [...], European Primary Care Vaccine Effectiveness Group.
Euro Surveill. 2024; 29 (13)
DOI: 10.2807/1560-7917.es.2024.29.13.2300403
BackgroundScarce European data in early 2021 suggested lower vaccine effectiveness (VE) against SARS-CoV-2 Omicron lineages than previous variants.AimWe aimed to estimate primary series (PS) and first booster VE against symptomatic BA.1/BA.2 infection and investigate potential biases.MethodsThis European test-negative multicentre study tested primary care patients with acute respiratory symptoms for SARS-CoV-2 in the BA.1/BA.2-dominant period. We estimated PS and booster VE among adults and adolescents (PS only) for all products combined and for Comirnaty alone, by time since vaccination, age and chronic condition. We investigated potential bias due to correlation between COVID-19 and influenza vaccination and explored effect modification and confounding by prior SARS-CoV-2 infection.ResultsAmong adults, PS VE was 37% (95% CI: 24-47%) overall and 60% (95% CI: 44-72%), 43% (95% CI: 26-55%) and 29% (95% CI: 13-43%) < 90, 90-179 and ≥ 180 days post vaccination, respectively. Booster VE was 42% (95% CI: 32-51%) overall and 56% (95% CI: 47-64%), 22% (95% CI: 2-38%) and 3% (95% CI: -78% to 48%), respectively. Primary series VE was similar among adolescents. Restricting analyses to Comirnaty had little impact. Vaccine effectiveness was higher among older adults. There was no signal of bias due to correlation between COVID-19 and influenza vaccination. Confounding by previous infection was low, but sample size precluded definite assessment of effect modification.ConclusionPrimary series and booster VE against symptomatic infection with BA.1/BA.2 ranged from 37% to 42%, with similar waning post vaccination. Comprehensive data on previous SARS-CoV-2 infection would help disentangle vaccine- and infection-induced immunity.
2024-03-01 2024 other research-article; Multicenter Study; Journal Article abstract-available 10.2807/1560-7917.es.2024.29.13.2300403 COVID-19 vaccine effectiveness against symptomatic infection with SARS-CoV-2 BA.1/BA.2 lineages among adults and adolescents in a multicentre primary care study, Europe, December 2021 to June 2022. Lanièce Delaunay C, Martínez-Baz I, Sève N, Domegan L, Mazagatos C, Buda S, Meijer A, Kislaya I, Pascu C, Carnahan A, Oroszi B, Ilić M, Maurel M, Melo A, Sandonis Martín V, Trobajo-Sanmartín C, Enouf V, McKenna A, Pérez-Gimeno G, Goerlitz L, de Lange M, Rodrigues AP, Lazar M, Latorre-Margalef N, Túri G, Castilla J, Falchi A, Bennett C, Gallardo V, Dürrwald R, Eggink D, Guiomar R, Popescu R, Riess M, Horváth JK, Casado I, García MDC, Hooiveld M, Machado A, Bacci S, Kaczmarek M, Kissling E, European Primary Care Vaccine Effectiveness Group. Euro Surveill. 2024; 29 (13)
Dextran sulfate from Leuconostoc mesenteroides B512F exerts potent antiviral activity against SARS-CoV-2 in vitro and in vivo.
Andreu S, von Kobbe C, Delgado P, Ripa I, [...], Bello-Morales R.
Front Microbiol. 2023; 14
DOI: 10.3389/fmicb.2023.1185504
The emergent human coronavirus SARS-CoV-2 and its resistance to current drugs makes the need for new potent treatments for COVID-19 patients strongly necessary. Dextran sulfate (DS) polysaccharides have long demonstrated antiviral activity against different enveloped viruses in vitro. However, their poor bioavailability has led to their abandonment as antiviral candidates. Here, we report for the first time the broad-spectrum antiviral activity of a DS-based extrapolymeric substance produced by the lactic acid bacterium Leuconostoc mesenteroides B512F. Time of addition assays with SARS-CoV-2 pseudoviruses in in vitro models confirm the inhibitory activity of DSs in the early stages of viral infection (viral entry). In addition, this exopolysaccharide substance also reports broad-spectrum antiviral activity against several enveloped viruses such as SARS-CoV-2, HCoV229E, HSV-1, in in vitro models and in human lung tissue. The toxicity and antiviral capacity of DS from L. mesenteroides was tested in vivo in mouse models which are susceptible to SARS-CoV-2 infection. The described DS, administered by inhalation, a new route of administration for these types of polymers, shows strong inhibition of SARS-CoV-2 infection in vivo, significantly reducing animal mortality and morbidity at non-toxic doses. Therefore, we suggest that it may be considered as a potential candidate for antiviral therapy against SARS-CoV-2.
2023-05-03 2023 other research-article; Journal Article abstract-available 10.3389/fmicb.2023.1185504 Dextran sulfate from <i>Leuconostoc mesenteroides</i> B512F exerts potent antiviral activity against SARS-CoV-2 <i>in vitro</i> and <i>in vivo</i>. Andreu S, von Kobbe C, Delgado P, Ripa I, Buzón MJ, Genescà M, Gironès N, Del Moral-Salmoral J, Ramírez GA, Zúñiga S, Enjuanes L, López-Guerrero JA, Bello-Morales R. Front Microbiol. 2023; 14
Dendritic Cell-Mediated Cross-Priming by a Bispecific Neutralizing Antibody Boosts Cytotoxic T Cell Responses and Protects Mice against SARS-CoV-2.
Lázaro-Gorines R, Pérez P, Heras-Murillo I, Adán-Barrientos I, [...], Álvarez-Vallina L.
Adv Sci (Weinh). 2023; 10 (34)
DOI: 10.1002/advs.202304818
Administration of neutralizing antibodies (nAbs) has proved to be effective by providing immediate protection against SARS-CoV-2. However, dual strategies combining virus neutralization and immune response stimulation to enhance specific cytotoxic T cell responses, such as dendritic cell (DC) cross-priming, represent a promising field but have not yet been explored. Here, a broadly nAb, TNT , are first generated by grafting an anti-RBD biparatopic tandem nanobody onto a trimerbody scaffold. Cryo-EM data show that the TNT structure allows simultaneous binding to all six RBD epitopes, demonstrating a high-avidity neutralizing interaction. Then, by C-terminal fusion of an anti-DNGR-1 scFv to TNT , the bispecific trimerbody TNT DNGR-1 is generated to target neutralized virions to type 1 conventional DCs (cDC1s) and promote T cell cross-priming. Therapeutic administration of TNT DNGR-1, but not TNT , protects K18-hACE2 mice from a lethal SARS-CoV-2 infection, boosting virus-specific humoral responses and CD8+ T cell responses. These results further strengthen the central role of interactions with immune cells in the virus-neutralizing antibody activity and demonstrate the therapeutic potential of the Fc-free strategy that can be used advantageously to provide both immediate and long-term protection against SARS-CoV-2 and other viral infections.
2023-10-20 2023 other research-article; Journal Article abstract-available 10.1002/advs.202304818 Dendritic Cell-Mediated Cross-Priming by a Bispecific Neutralizing Antibody Boosts Cytotoxic T Cell Responses and Protects Mice against SARS-CoV-2. Lázaro-Gorines R, Pérez P, Heras-Murillo I, Adán-Barrientos I, Albericio G, Astorgano D, Flores S, Luczkowiak J, Labiod N, Harwood SL, Segura-Tudela A, Rubio-Pérez L, Nugraha Y, Shang X, Li Y, Alfonso C, Adipietro KA, Abeyawardhane DL, Navarro R, Compte M, Yu W, MacKerell AD, Sanz L, Weber DJ, Blanco FJ, Esteban M, Pozharski E, Godoy-Ruiz R, Muñoz IG, Delgado R, Sancho D, García-Arriaza J, Álvarez-Vallina L. Adv Sci (Weinh). 2023; 10 (34)
VIPERA: Viral Intra-Patient Evolution Reporting and Analysis.
Álvarez-Herrera M, Sevilla J, Ruiz-Rodriguez P, Vergara A, [...], Coscollá M.
Virus Evol. 2024; 10 (1)
DOI: 10.1093/ve/veae018
Viral mutations within patients nurture the adaptive potential of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during chronic infections, which are a potential source of variants of concern. However, there is no integrated framework for the evolutionary analysis of intra-patient SARS-CoV-2 serial samples. Herein, we describe Viral Intra-Patient Evolution Reporting and Analysis (VIPERA), a new software that integrates the evaluation of the intra-patient ancestry of SARS-CoV-2 sequences with the analysis of evolutionary trajectories of serial sequences from the same viral infection. We have validated it using positive and negative control datasets and have successfully applied it to a new case, which revealed population dynamics and evidence of adaptive evolution. VIPERA is available under a free software license at https://github.com/PathoGenOmics-Lab/VIPERA.
2024-03-06 2024 other research-article; Journal Article abstract-available 10.1093/ve/veae018 VIPERA: Viral Intra-Patient Evolution Reporting and Analysis. Álvarez-Herrera M, Sevilla J, Ruiz-Rodriguez P, Vergara A, Vila J, Cano-Jiménez P, González-Candelas F, Comas I, Coscollá M. Virus Evol. 2024; 10 (1)
Endodontic variables in patients with SARS-CoV-2 infection (COVID-19) in relation to the severity of the disease.
Poyato-Borrego M, León-López M, Martín-González J, Cisneros-Herreros JM, [...], Segura-Egea JJ.
Med Oral Patol Oral Cir Bucal. 2023; 28 (4)
DOI: 10.4317/medoral.25773

Background

Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) is the cause of the ongoing coronavirus disease 2019 (COVID-19) pandemic. It has been hypothesized oral health may be related to the severity and complications of COVID-19. The aim of this study was to analyze the prevalence of apical periodontitis and the frequency of root canal treatment in a sample of patients with SARS-CoV-2 infection (COVID-19), correlating them with the severity of the disease.

Material and methods

This retrospective study was conducted following the Strengthening Reporting Observational Studies in Epidemiology (STROBE) guidelines. The study examined 280 patients with positive real time PCR COVID-19 test whose treatment was performed in our hospital. Fifty-two patients aged 52.3 ± 17.3 years, including 30 males and 22 females, who had an orthopantomography in their clinical record, performed in the last 2 years, were included. Patients with SARS-CoV-2 infection were grouped as mild or moderate (MM) and severe or critical (SC) illness groups, according to the NIH COVID-19 Treatment Guidelines (Wu & McGoogan 2020). Radiographic records were analyzed and apical periodontitis (AP) was diagnosed as radiolucent periapical lesions (RPLs), using the periapical index score (PAI). Student's t test, χ2 test and multivariate logistic regression were used in the statistical analysis.

Results

The number of carious teeth was significantly higher in the SC group (3.4 ± 4.1), which showed more than twice as many teeth with carious lesions than the MM group (1.4 ± 1.8) (p = 0.02). Multivariate regression analysis showed association between the number of carious teeth and the severity of SARS-CoV-2 disease (OR = 1.5; 95% CI = 1.1-2.1; p = 0.017). Endodontic status (OR = 7.12; 95% CI = 1.2-40.9; p = 0.027) also correlated with the disease severity.

Conclusions

The results suggest that the oral health status of COVID-19 patients correlated with the severity of the SARS-CoV-2 virus infection. Significant association has been found between the severity of COVID-19 disease and the presence of a greater number of teeth with caries lesions, as well as with endodontic status.
2023-07-01 2023 other research-article; Journal Article; Observational Study abstract-available 10.4317/medoral.25773 Endodontic variables in patients with SARS-CoV-2 infection (COVID-19) in relation to the severity of the disease. Poyato-Borrego M, León-López M, Martín-González J, Cisneros-Herreros JM, Cabanillas-Balsera D, Segura-Egea JJ. Med Oral Patol Oral Cir Bucal. 2023; 28 (4)
The importance of translational science within the respiratory field.
Meiners S, Reynaert NL, Matthaiou AM, Rajesh R, [...], Cuevas-Ocaña S.
Breathe (Sheff). 2024; 20 (1)
DOI: 10.1183/20734735.0183-2023
The Translational Science Working Group at the European Respiratory Society (ERS) aims to bridge the gap between basic and clinical science by providing a platform where scientists, clinicians and experts in the respiratory field can actively shape translational research. For the 2023 Congress, dedicated translational science sessions were created and sessions of interest to many assemblies from the clinical and the scientific point of view were tagged as translational sessions, attracting clinical and scientific experts to the same room to discuss relevant topics and strengthening translational efforts among all ERS assemblies.
2024-03-01 2024 other research-article; Journal Article abstract-available 10.1183/20734735.0183-2023 The importance of translational science within the respiratory field. Meiners S, Reynaert NL, Matthaiou AM, Rajesh R, Ahmed E, Guillamat-Prats R, Heijink IH, Cuevas-Ocaña S. Breathe (Sheff). 2024; 20 (1)
Update of the current knowledge on genetics, evolution, immunopathogenesis, and transmission for coronavirus disease 19 (COVID-19).
Tizaoui K, Zidi I, Lee KH, Ghayda RA, [...], Shin JI.
Int J Biol Sci. 2020; 16 (15)
DOI: 10.7150/ijbs.48812
In December 2019, an acute respiratory disease caused by novel species of coronavirus (SARS-CoV-2), emerged in China and has spread throughout the world. On 11th March 2020, the World Health Organization (WHO) officially declared coronavirus disease 19 (COVID-19) a pandemic, severe coronavirus-mediated human disease. Based on genomic and phylogenetic studies, SARS-CoV-2 might originate from bat coronaviruses and infects humans directly or through intermediate zoonotic hosts. However, the exact origin or the host intermediate remains unknown. Genetically, SARS-CoV-2 is similar to several existing coronaviruses, particularly SARS-CoV, but differs by silent and non-silent mutations. The virus uses different transmission routes and targets cells and tissues with angiotensin-converting enzyme 2 (ACE2) protein, which makes it contagious. COVID-19 shares both the main clinical features and excessive/dysregulated cell responses with the two previous Middle East respiratory syndrome coronavirus (MERS) and severe acute respiratory syndrome coronavirus (SARS) epidemics. In this review, we provide an update of the current knowledge on the COVID-19 pandemic. Gaining a deeper understanding of SARS-CoV-2 structure, transmission routes, and molecular responses, will assist in the prevention and control of COVID-19 outbreaks in the future.
2020-09-12 2020 other review-article; Review; Journal Article abstract-available 10.7150/ijbs.48812 Update of the current knowledge on genetics, evolution, immunopathogenesis, and transmission for coronavirus disease 19 (COVID-19). Tizaoui K, Zidi I, Lee KH, Ghayda RA, Hong SH, Li H, Smith L, Koyanagi A, Jacob L, Kronbichler A, Shin JI. Int J Biol Sci. 2020; 16 (15)
Diabetes Ketoacidosis and COVID-19: An Insight into the Pathophysiology.
Ahadiat SA, Hosseinian Z.
Int J Endocrinol Metab. 2023; 21 (2)
DOI: 10.5812/ijem-133631
2023-04-04 2023 other letter; Journal Article 10.5812/ijem-133631 Diabetes Ketoacidosis and COVID-19: An Insight into the Pathophysiology. Ahadiat SA, Hosseinian Z. Int J Endocrinol Metab. 2023; 21 (2)
Role of Dipeptidyl Peptidase-4 (DPP4) on COVID-19 Physiopathology.
Sebastián-Martín A, Sánchez BG, Mora-Rodríguez JM, Bort A, [...], Díaz-Laviada I.
Biomedicines. 2022; 10 (8)
DOI: 10.3390/biomedicines10082026
DPP4/CD26 is a single-pass transmembrane protein with multiple functions on glycemic control, cell migration and proliferation, and the immune system, among others. It has recently acquired an especial relevance due to the possibility to act as a receptor or co-receptor for SARS-CoV-2, as it has been already demonstrated for other coronaviruses. In this review, we analyze the evidence for the role of DPP4 on COVID-19 risk and clinical outcome, and its contribution to COVID-19 physiopathology. Due to the pathogenetic links between COVID-19 and diabetes mellitus and the hyperinflammatory response, with the hallmark cytokine storm developed very often during the disease, we dive deep into the functions of DPP4 on carbohydrate metabolism and immune system regulation. We show that the broad spectrum of functions regulated by DPP4 is performed both as a protease enzyme, as well as an interacting partner of other molecules on the cell surface. In addition, we provide an update of the DPP4 inhibitors approved by the EMA and/or the FDA, together with the newfangled approval of generic drugs (in 2021 and 2022). This review will also cover the effects of DPP4 inhibitors (i.e., gliptins) on the progression of SARS-CoV-2 infection, showing the role of DPP4 in this disturbing disease.
2022-08-19 2022 other review-article; Review; Journal Article abstract-available 10.3390/biomedicines10082026 Role of Dipeptidyl Peptidase-4 (DPP4) on COVID-19 Physiopathology. Sebastián-Martín A, Sánchez BG, Mora-Rodríguez JM, Bort A, Díaz-Laviada I. Biomedicines. 2022; 10 (8)
Serum angiotensin-converting enzyme 2 as a potential biomarker for SARS-CoV-2 infection and vaccine efficacy.
Lennol MP, García-Ayllón MS, Esteban M, García-Arriaza J, [...], Sáez-Valero J.
Front Immunol. 2022; 13
DOI: 10.3389/fimmu.2022.1001951
Various species of the SARS-CoV-2 host cell receptor, the angiotensin-converting enzyme 2 (ACE2), are present in serum, which may result from virus entry and subsequent proteolytic processing of the membrane receptor. We have recently demonstrated changes of particular ACE2 species in virus infected humans, either cleaved fragments or circulating full-length species. Here, we further explore the potential of serum ACE2 as a biomarker to test SARS-CoV-2 infection and vaccine efficacy in virus susceptible transgenic K18-hACE2 mice expressing human ACE2. First, in serum samples derived from K18-hACE2 mice challenged with a lethal dose of SARS-CoV-2, we observed an increase in the levels of cleaved ACE2 fragment at day 2 post-challenge, which may represent the subsequent proteolytic processing through virus entry. These elevated levels were maintained until the death of the animals at day 6 post-challenge. The circulating full-length ACE2 form displayed a sizable peak at day 4, which declined at day 6 post-challenge. Noticeably, immunization with two doses of the MVA-CoV2-S vaccine candidate prevented ACE2 cleaved changes in serum of animals challenged with a lethal dose of SARS-CoV-2. The efficacy of the MVA-CoV2-S was extended to vaccinated mice after virus re-challenge. These findings highlight that ACE2 could be a potential serum biomarker for disease progression and vaccination against SARS-CoV-2.
2022-10-12 2022 other brief-report; Research Support, Non-U.S. Gov't; Journal Article abstract-available 10.3389/fimmu.2022.1001951 Serum angiotensin-converting enzyme 2 as a potential biomarker for SARS-CoV-2 infection and vaccine efficacy. Lennol MP, García-Ayllón MS, Esteban M, García-Arriaza J, Sáez-Valero J. Front Immunol. 2022; 13
Immune responses and clinical outcomes after COVID-19 vaccination in patients with liver disease and liver transplant recipients
Murray S, Pose E, Wittner M, Londoño M, [...], Marjot T.
J Hepatol. 2024; 80 (1)
DOI:
2024-01-01 2024 other research-article; Journal Article Immune responses and clinical outcomes after COVID-19 vaccination in patients with liver disease and liver transplant recipients Murray S, Pose E, Wittner M, Londoño M, Schaub G, Cook J, Dimitriadis S, Meacham G, Irwin S, Lim Z, Duengelhoef P, Sterneck M, Lohse A, Perez V, Trivedi P, Bhandal K, Mullish B, Manousou P, Provine N, Avitabile E, Carroll M, Tipton T, Healy S, Burra P, Klenerman P, Dunachie S, Kronsteiner B, Maciola A, Pasqual G, Hernandez-Gea V, Garcia-Pagan J, Lampertico P, Iavarone M, Gines P, Lütgehetmann M, Schulze zur Wiesch J, Russo F, Barnes E, Marjot T. J Hepatol. 2024; 80 (1)
Network pharmacology reveals multitarget mechanism of action of drugs to be repurposed for COVID-19.
Alegría-Arcos M, Barbosa T, Sepúlveda F, Combariza G, [...], Ramírez D.
Front Pharmacol. 2022; 13
DOI: 10.3389/fphar.2022.952192
The coronavirus disease 2019 pandemic accelerated drug/vaccine development processes, integrating scientists all over the globe to create therapeutic alternatives against this virus. In this work, we have collected information regarding proteins from SARS-CoV-2 and humans and how these proteins interact. We have also collected information from public databases on protein-drug interactions. We represent this data as networks that allow us to gain insights into protein-protein interactions between both organisms. With the collected data, we have obtained statistical metrics of the networks. This data analysis has allowed us to find relevant information on which proteins and drugs are the most relevant from the network pharmacology perspective. This method not only allows us to focus on viral proteins as the main targets for COVID-19 but also reveals that some human proteins could be also important in drug repurposing campaigns. As a result of the analysis of the SARS-CoV-2-human interactome, we have identified some old drugs, such as disulfiram, auranofin, gefitinib, suloctidil, and bromhexine as potential therapies for the treatment of COVID-19 deciphering their potential complex mechanism of action.
2022-08-17 2022 other research-article; Journal Article abstract-available 10.3389/fphar.2022.952192 Network pharmacology reveals multitarget mechanism of action of drugs to be repurposed for COVID-19. Alegría-Arcos M, Barbosa T, Sepúlveda F, Combariza G, González J, Gil C, Martínez A, Ramírez D. Front Pharmacol. 2022; 13
European Society of Cardiology guidance for the diagnosis and management of cardiovascular disease during the COVID-19 pandemic: part 1-epidemiology, pathophysiology, and diagnosis.
Task Force for the management of COVID-19 of the European Society of Cardiology, Baigent C, Windecker S, Andreini D, [...], Williams B.
Cardiovasc Res. 2022; 118 (6)
DOI: 10.1093/cvr/cvab342

Aims

Since its emergence in early 2020, the novel severe acute respiratory syndrome coronavirus 2 causing coronavirus disease 2019 (COVID-19) has reached pandemic levels, and there have been repeated outbreaks across the globe. The aim of this two-part series is to provide practical knowledge and guidance to aid clinicians in the diagnosis and management of cardiovascular disease (CVD) in association with COVID-19.

Methods and results

A narrative literature review of the available evidence has been performed, and the resulting information has been organized into two parts. The first, reported here, focuses on the epidemiology, pathophysiology, and diagnosis of cardiovascular (CV) conditions that may be manifest in patients with COVID-19. The second part, which will follow in a later edition of the journal, addresses the topics of care pathways, treatment, and follow-up of CV conditions in patients with COVID-19.

Conclusion

This comprehensive review is not a formal guideline but rather a document that provides a summary of current knowledge and guidance to practicing clinicians managing patients with CVD and COVID-19. The recommendations are mainly the result of observations and personal experience from healthcare providers. Therefore, the information provided here may be subject to change with increasing knowledge, evidence from prospective studies, and changes in the pandemic. Likewise, the guidance provided in the document should not interfere with recommendations provided by local and national healthcare authorities.
2022-05-01 2022 other research-article; Review; Journal Article abstract-available 10.1093/cvr/cvab342 European Society of Cardiology guidance for the diagnosis and management of cardiovascular disease during the COVID-19 pandemic: part 1-epidemiology, pathophysiology, and diagnosis. Task Force for the management of COVID-19 of the European Society of Cardiology, Baigent C, Windecker S, Andreini D, Arbelo E, Barbato E, Bartorelli AL, Baumbach A, Behr ER, Berti S, Bueno H, Capodanno D, Cappato R, Chieffo A, Collet JP, Cuisset T, de Simone G, Delgado V, Dendale P, Dudek D, Edvardsen T, Elvan A, González-Juanatey JR, Gori M, Grobbee D, Guzik TJ, Halvorsen S, Haude M, Heidbuchel H, Hindricks G, Ibanez B, Karam N, Katus H, Klok FA, Konstantinides SV, Landmesser U, Leclercq C, Leonardi S, Lettino M, Marenzi G, Mauri J, Metra M, Morici N, Mueller C, Petronio AS, Polovina MM, Potpara T, Praz F, Prendergast B, Prescott E, Price S, Pruszczyk P, Rodríguez-Leor O, Roffi M, Romaguera R, Rosenkranz S, Sarkozy A, Scherrenberg M, Seferovic P, Senni M, Spera FR, Stefanini G, Thiele H, Tomasoni D, Torracca L, Touyz RM, Wilde AA, Williams B. Cardiovasc Res. 2022; 118 (6)
Inflammation in COVID-19 and the Effects of Non-Pharmacological Interventions during the Pandemic: A Review.
Clemente-Suárez VJ, Bustamante-Sanchez Á, Tornero-Aguilera JF, Ruisoto P, [...], Mielgo-Ayuso J.
Int J Mol Sci. 2022; 23 (24)
DOI: 10.3390/ijms232415584
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the coronavirus disease 2019 (COVID-19) pandemic that hit the health systems worldwide hard, causing a collapse of healthcare systems. One of the main problems of this new virus is the high inflammatory response it provokes, which is the cause of much of the symptoms. Different pharmacological approaches tried to stop the advance of the pandemic, but it seems that only vaccines are the solution. In this line, different nonpharmacological approaches have been made in order to improve symptomatology, contagion, and spread of COVID-19, the principal factors being the physical activity, nutrition, physiotherapy, psychology, and life patterns. The SARS-CoV-2 virus produces a disproportionate inflammatory response in the organism of the guest and causes complications in this that can end the life of the patient. It has been possible to see how different nonpharmacological interventions based on physical activity, nutritional, psychological, and physical therapy, and lifestyle changes can be functional tools to treat this inflammation. Thus, in the present review, we aim to provide an overview of the role of inflammation in COVID-19 and the nonpharmacological interventions related to it.
2022-12-09 2022 other review-article; Review; Journal Article abstract-available 10.3390/ijms232415584 Inflammation in COVID-19 and the Effects of Non-Pharmacological Interventions during the Pandemic: A Review. Clemente-Suárez VJ, Bustamante-Sanchez Á, Tornero-Aguilera JF, Ruisoto P, Mielgo-Ayuso J. Int J Mol Sci. 2022; 23 (24)
C-2 Thiophenyl Tryptophan Trimers Inhibit Cellular Entry of SARS-CoV-2 through Interaction with the Viral Spike (S) Protein.
Gargantilla M, Francés C, Adhav A, Forcada-Nadal A, [...], Pérez-Pérez MJ.
J Med Chem. 2023; 66 (15)
DOI: 10.1021/acs.jmedchem.3c00576
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, by infecting cells via the interaction of its spike protein (S) with the primary cell receptor angiotensin-converting enzyme (ACE2). To search for inhibitors of this key step in viral infection, we screened an in-house library of multivalent tryptophan derivatives. Using VSV-S pseudoparticles, we identified compound 2 as a potent entry inhibitor lacking cellular toxicity. Chemical optimization of 2 rendered compounds 63 and 65, which also potently inhibited genuine SARS-CoV-2 cell entry. Thermofluor and microscale thermophoresis studies revealed their binding to S and to its isolated receptor binding domain (RBD), interfering with the interaction with ACE2. High-resolution cryoelectron microscopy structure of S, free or bound to 2, shed light on cell entry inhibition mechanisms by these compounds. Overall, this work identifies and characterizes a new class of SARS-CoV-2 entry inhibitors with clear potential for preventing and/or fighting COVID-19.
2023-07-20 2023 fondo-covid Research Support, Non-U.S. Gov't; research-article; Journal Article abstract-available 10.1021/acs.jmedchem.3c00576 C-2 Thiophenyl Tryptophan Trimers Inhibit Cellular Entry of SARS-CoV-2 through Interaction with the Viral Spike (S) Protein. Gargantilla M, Francés C, Adhav A, Forcada-Nadal A, Martínez-Gualda B, Martí-Marí O, López-Redondo ML, Melero R, Marco-Marín C, Gougeard N, Espinosa C, Rubio-Del-Campo A, Ruiz-Partida R, Hernández-Sierra MDP, Villamayor-Belinchón L, Bravo J, Llacer JL, Marina A, Rubio V, San-Félix A, Geller R, Pérez-Pérez MJ. J Med Chem. 2023; 66 (15)
Risk of herpes zoster in adults with SARS-CoV-2 infection in Spain: A population-based, retrospective cohort study.
Correcher-Martínez E, López-Lacort M, Muñoz-Quiles C, Díez-Domingo J, [...], Orrico-Sánchez A.
Int J Infect Dis. 2024; 143
DOI: 10.1016/j.ijid.2024.107037

Objectives

We aimed to compare the risk of herpes zoster (HZ) in adults with and without laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

Methods

This retrospective dynamic cohort study analyzed data from a public healthcare database in Spain between November 2020 and October 2021. The main outcome was incident cases of HZ in individuals ≥18-year-old. Relative risk (RR) of HZ in SARS-CoV-2-confirmed versus SARS-CoV-2-free individuals was estimated by a multivariable negative binomial regression adjusted by age, sex, and comorbidities.

Results

Data from 4,085,590 adults were analyzed. The overall HZ incidence rate in adults was 5.76 (95% confidence interval [CI], 5.66-5.85) cases per 1000 person-years. Individuals ≥18-year-old with SARS-CoV-2-confirmed infection had a 19% higher risk of developing HZ versus SARS-CoV-2-free ≥18-year-olds (adjusted RR = 1.19; 95% CI, 1.09-1.29); this percentage was 16% (adjusted RR = 1.16; 95% CI, 1.05-1.29) in ≥50-year-olds. Severe (hospitalized) cases of SARS-CoV-2 infection had a 64% (if ≥18 years old) or 44% (if ≥50 years old) higher risk of HZ versus nonhospitalized cases.

Conclusion

These results support an association between SARS-CoV-2 infection and HZ, with a greater HZ risk in severe cases of SARS-CoV-2 infection.
2024-04-02 2024