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DeDiego ML, López-Fernández-Sobrino R, Pedragosa J, López-García D, Nogales A, Durbán J, Cardona F, Llucià-Carol L, Rivero V, Vazquez-Utrilla P, Sanchez-Grande LP, Cobo M, Lloret L, Márquez-Kisinousky L, Ruiz-Jaén F, Lozano F, Sibila O, Faner R, Castro P, Domingo C, Robles V, Bedini JL, Rico V, Aguero D, Soriano A, Nalda AM, Martínez AP, Colobran R, Soler-Palacín P, Serra-Llovich A, Dietl B, Arranz MJ, Dalmau D, Signes-Costa J, Gil-Carbonell J, Todolí J, Martínez J, Rojo S, Fiz-López A, Arribas E, Cal-Sabater P, Bernado D, Vogel M, Wiemann S, Abolhassani H, Pan-Hammarström Q, Pujol A, COVID Human Genetic Effort , Su HC, Lee D, Zhang SY, Casanova JL, Fernández-Cadenas I, Pérez-Tur J, Planas AM
iScience 28 (12) 113966 [2025-12-19; online 2025-11-11]
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 OAS1/OAS3 variants and the common OAS1 rs10774671 polymorphism in 342 COVID-19 patients, assessing enzymatic activity, RNase L activation, viral replication, and inflammation in cell systems and Oas3-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 (OR = 2.28; 95% CI = 1.13-4.58; p = 0.0107) and reduced viral control despite intact RNase L activation. OAS3 and OAS1-p46 isoform limited viral replication and inflammatory responses, whereas Oas3-deficient mice showed increased cytokines. These findings suggest that common OAS1 variation influences COVID-19 severity, while rare OAS variants may affect inflammation regulation rather than respiratory pathology.
PubMed 41438061
DOI 10.1016/j.isci.2025.113966
Crossref 10.1016/j.isci.2025.113966
pmc: PMC12719101
pii: S2589-0042(25)02227-8