Background: Recessive deficiency in 2’,5’-oligoadenylate (2-5A) synthetase (OAS) or RNase L can underlie multisystem inflammatory syndrome associated with SARS-CoV-2 infection in children without pneumonia. In adult COVID-19 patients, common genetic variants at the OAS locus were associated with hypoxemic pneumonia. Since the role of OAS in respiratory pathology versus inflammation remains unclear, we investigated OAS variants found in adult COVID-19 patients.

Methods: We analyzed the association of rare OAS1 and OAS3 variants and the common OAS1 rs10774671 polymorphism with clinical severity in 342 COVID-19 patients. We assessed OAS enzymatic activity and RNase L activation by SARS-CoV-2 or synthetic dsRNA, and the impact of gene gain/loss-of-function on viral replication and inflammation. The latter effects were also studied in Oas3^-/- mice challenged with dsRNA or mouse-adapted SARS-CoV-2.

Findings: Nine OAS1 and 15 OAS3 heterozygous variants were predicted to be deleterious. Although several variants displayed defective RNase L activation in response to SARS-CoV-2 or dsRNA, enrichment analysis showed no clear association with COVID-19 pneumonia. However, the OAS1 rs10774671 A/A genotype (OAS1-p42 isoform) was correlated with severe disease. Overexpression of OAS3 and OAS1-p46 isoforms attenuated viral replication in cellular systems, while OAS1-p42 reduced this effect. OAS3 and OAS1-p46 limited inflammatory response, and Oas3-deficiency in mice increased cytokine expression.

Interpretation: OAS1 rs10774671 A/A genotype impaired viral control, despite preserving RNase L activation, and predominated in severe COVID-19 patients. Conversely, heterozygous rare loss-of-function OAS1 and OAS3 variants appeared unrelated to respiratory disease severity, but they may compromise a regulatory mechanism that fine-tunes the control of inflammation.