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Inherited genetic factors can influence the severity of COVID-19, but the molecular explanation underpinning a genetic association is often unclear. Intracellular antiviral defenses can inhibit the replication of viruses and reduce disease severity. To better understand the antiviral defenses relevant to COVID-19, we used interferon-stimulated gene (ISG) expression screening to reveal that 2′-5′-oligoadenylate synthetase 1 (OAS1), through ribonuclease L, potently inhibits severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We show that a common splice-acceptor single-nucleotide polymorphism (Rs10774671) governs whether patients express prenylated OAS1 isoforms that are membrane-associated and sense-specific regions of SARS-CoV-2 RNAs or if they only express cytosolic, nonprenylated OAS1 that does not efficiently detect SARS-CoV-2. In hospitalized patients, expression of prenylated OAS1 was associated with protection from severe COVID-19, suggesting that this antiviral defense is a major component of a protective antiviral response.

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2',5'-Oligoadenylate Synthetase, 5' Untranslated Regions, A549 Cells, Animals, COVID-19, Chiroptera, Coronaviridae, Endoribonucleases, Humans, Interferons, Isoenzymes, Phosphoric Diester Hydrolases, Polymorphism, Single Nucleotide, Protein Prenylation, RNA, Double-Stranded, RNA, Viral, Retroelements, SARS-CoV-2, Severity of Illness Index, Virus Replication