OAS1 and OAS3 genetic variants enhance inflammatory responses to SARS-CoV-2

Recessive deficiency in 2',5'-oligoadenylate synthetase (OAS) or RNase L can cause systemic inflammation in children with SARS-CoV-2 infection, but its role in adult respiratory disease is unclear. We analyzed rare <i>OAS1/OAS3</i> variants and the common <i>OAS1</i> rs10774671 polymorphism in 342 COVID-19 patients, assessing enzymatic activity, RNase L activation, viral replication, and inflammation in cell systems and <i>Oas3</i>-deficient mice. Rare heterozygous variants showed impaired RNase L activation but were not enriched in pneumonia cases. In contrast, the rs10774671 A/A genotype (OAS1-p42 isoform) was associated with severe disease (<i>OR</i> = 2.28; 95% CI = 1.13-4.58; <i>p</i> = 0.0107) and reduced viral control despite intact RNase L activation. OAS3 and OAS1-p46 isoform limited viral replication and inflammatory responses, whereas <i>Oas3</i>-deficient mice showed increased cytokines. These findings suggest that common <i>OAS1</i> variation influences COVID-19 severity, while rare <i>OAS</i> variants may affect inflammation regulation rather than respiratory pathology.

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Publication Details

Journal
iScience
Published
2025-11-13
DOI
https://doi.org/10.1016/j.isci.2025.113966
Citations
1
Primary Topic
Amyotrophic Lateral Sclerosis Research
Type
article
Field-Weighted Citation Impact
1.39
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article

OAS1 and OAS3 genetic variants enhance inflammatory responses to SARS-CoV-2

Aida Fiz‐López, Pere Soler‐Palacín, Leonardo Márquez‐Kisinousky, Fernando Cardona et al.
1 citations
iScience
Amyotrophic Lateral Sclerosis Research
1.39
article

OAS1 and OAS3 genetic variants enhance inflammatory responses to SARS-CoV-2

Aida Fiz‐López, Pere Soler‐Palacín, Leonardo Márquez‐Kisinousky, Fernando Cardona, Helen C. Su, Stefan Wiemann, Vanessa Rivero, Joan Gil-Carbonell, Àlex Soriano, Danyel Lee, Oriol Sibila, Laia Llucià‐Carol, Josep Lluís Bedini, Marina Vogel, Miriam Cobo, Elisa Arribas‐Rodríguez, Alba Parra-Martínez, Jean‐Laurent Casanova, Hassan Abolhassani, Verónica Robles, Jaime Signes‐Costa, Rosa Faner, Roger Colobrán, L. Lloret Iglesias, Aitor Nogales, Qiang Pan‐Hammarström, Paloma Cal‐Sabater, Marta L. DeDiego, Francisca Ruíz-Jaén, Jordi Pérez‐Tur, Shen‐Ying Zhang, Anna M. Planas, Daiana Agüero, Aurora Pujol, Beatriz Dietl, Jordi Durbán, Israel Fernández‐Cadenas, Alex Serra-Llovich, Verónica Rico, Darío López-García, Pedro Castro, Francisco S. Lozano, David Dalmau, Andrea Martín-Nalda, Paula Vázquez-Utrilla, José Todolí, Carlos Domingo, Silvia Rojo, Juan J. Martinez, Raúl López-Fernández-Sobrino, Laura Palomo Sanchez-Grande, Jordi Pedragosa, David Bernado
article en
1 citations

Abstract

Recessive deficiency in 2',5'-oligoadenylate synthetase (OAS) or RNase L can cause systemic inflammation in children with SARS-CoV-2 infection, but its role in adult respiratory disease is unclear. We analyzed rare <i>OAS1/OAS3</i> variants and the common <i>OAS1</i> rs10774671 polymorphism in 342 COVID-19 patients, assessing enzymatic activity, RNase L activation, viral replication, and inflammation in cell systems and <i>Oas3</i>-deficient mice. Rare heterozygous variants showed impaired RNase L activation but were not enriched in pneumonia cases. In contrast, the rs10774671 A/A genotype (OAS1-p42 isoform) was associated with severe disease (<i>OR</i> = 2.28; 95% CI = 1.13-4.58; <i>p</i> = 0.0107) and reduced viral control despite intact RNase L activation. OAS3 and OAS1-p46 isoform limited viral replication and inflammatory responses, whereas <i>Oas3</i>-deficient mice showed increased cytokines. These findings suggest that common <i>OAS1</i> variation influences COVID-19 severity, while rare <i>OAS</i> variants may affect inflammation regulation rather than respiratory pathology.

iScienceVol. 28(12)
Institució Catalana de Recerca i Estudis Avançats (ES), Hebron University (PS), Howard Hughes Medical Institute (US), Consejo Superior de Investigaciones Científicas (ES), Inserm (FR), German Cancer Research Center (DE), Heidelberg University (DE), Science for Life Laboratory (SE), Instituto de Salud Carlos III (ES), Hospital de Sant Pau (ES), Karolinska Institutet (SE), Hospital Universitari i Politècnic La Fe (ES), Institut d'Investigació Biomédica de Bellvitge (ES), Hospital Universitari Sant Joan D'Alacant (ES), Hospital Clínico Universitario de Valencia (ES), Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (ES), Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (ES), Vall d'Hebron Institut de Recerca (ES), Centro Nacional de Biotecnología (ES), Centre for Biomedical Network Research on Rare Diseases (ES), Centro de Investigación Biomédica en Red (ES), Hospital Clínic de Barcelona (ES), Institut d'Investigacions Biomèdiques de Barcelona (ES), Vall d'Hebron Hospital Universitari (ES), Mútua Terrassa (ES), National Institute of Allergy and Infectious Diseases (US), Instituto de Biomedicina y Genética Molecular de Valladolid (ES), Office of Extramural Research (US), Instituto de Biomedicina de Valencia (ES), Instituto de Física de Cantabria (ES), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), Institut des Maladies Génétiques Imagine (FR), Institut de Recerca Sant Pau (ES), Universidad Autónoma de Madrid (ES), University of Pennsylvania (US), Rockefeller University (US)
Openalex Percentile: Top 14%
Amyotrophic Lateral Sclerosis Research
1.39
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