DeDiego, Marta L.López Fernández Sobrino, RaúlPedragosa, JordiLópez García, DaríoNogales, AitorDurbán, JordiCardona, FernandoLlucià Carol, LaiaRivero, VanessaVazquez Utrilla, PaulaPalomo Sanchez Grande, LauraCobo, MiriamLloret, LaraMárquez Kisinousky, LeonardoRuiz Jaén, FranciscaLozano, FranciscoSibila, OriolFaner, RosaCastro, PedroDomingo, CarlosRobles, VerónicaBedini, Josep L.Rico, VerónicaAguero, DaianaSoriano, AlexMartín Nalda, AndreaParra Martínez, AlbaColobran, RogerSoler Palacín, PereSerra Llovich, AlexandreDietl, BeatrizJesús Arranz, M.Dalmau, DavidSignes Costa, JaimeGil Carbonell, JoanTodolí, JoséMartínez, JacoboRojo, SilviaFiz López, AidaArribas, ElisaCal Sabater, PalomaBernado, DavidVogel, MarinaWiemann, StefanAbolhassani, HassanPan-hammarström, QiangPujol, AuroraSu, Helen C.Lee, DanyelZhang, Shen YingCasanova, Jean LaurentFernández Cadenas, IsraelPérez Tur, JordiPlanas, Anna M.2026-04-102026-04-102025-11-13https://hdl.handle.net/2445/228785Recessive 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.35 p.application/pdfengcc-by-nc-nd (c) DeDiego, Marta L. et al., 2025https://creativecommons.org/licenses/by-nc-nd/4.0/SARS-CoV-2Síndromes de deficiència immunitàriaMalalties de l'aparell respiratori en els infantsSARS-CoV-2Immunological deficiency syndromesRespiratory diseases in childreninfo:eu-repo/semantics/article2026-02-09info:eu-repo/semantics/openAccess41438061