and genetic variants enhance inflammatory responses to SARS-CoV-2.

Publications

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 variants and the common rs10774671 polymorphism in 342 COVID-19 patients, assessing enzymatic activity, RNase L activation, viral replication, and inflammation in cell systems and -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 ( = 2.28; 95% CI = 1.13-4.58; = 0.0107) and reduced viral control despite intact RNase L activation. OAS3 and OAS1-p46 isoform limited viral replication and inflammatory responses, whereas -deficient mice showed increased cytokines. These findings suggest that common variation influences COVID-19 severity, while rare variants may affect inflammation regulation rather than respiratory pathology.

DOI: 10.1016/j.isci.2025.113966, PMID: 41438061
Authors: Marta L DeDiego, Raúl López-Fernández-Sobrino, Jordi Pedragosa, Darío López-García, Aitor Nogales, Jordi Durbán, Fernando Cardona, Laia Llucià-Carol, Vanessa Rivero, Paula Vazquez-Utrilla, Laura Palomo Sanchez-Grande, Miriam Cobo, Lara Lloret, Leonardo Márquez-Kisinousky, Francisca Ruiz-Jaén, Francisco Lozano, Oriol Sibila, Rosa Faner, Pedro Castro, Carlos Domingo, Verónica Robles, Josep L Bedini, Verónica Rico, Daiana Aguero, Alex Soriano, Andrea Martín Nalda, Alba Parra Martínez, Roger Colobran, Pere Soler-Palacín, Alexandre Serra-Llovich, Beatriz Dietl, M Jesús Arranz, David Dalmau, Jaime Signes-Costa, Joan Gil-Carbonell, José Todolí, Jacobo Martínez, Silvia Rojo, Aida Fiz-López, Elisa Arribas, Paloma Cal-Sabater, David Bernado, Marina Vogel, Stefan Wiemann, Hassan Abolhassani, Qiang Pan-Hammarström, Aurora Pujol, Helen C Su, Danyel Lee, Shen-Ying Zhang, Jean-Laurent Casanova, Israel Fernández-Cadenas, Jordi Pérez-Tur, Anna M Planas