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A prenylated dsRNA sensor protects against severe COVID-19.

ABSTRACT: 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.

SUBMITTER: Wickenhagen A 

PROVIDER: S-EPMC7612834 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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A prenylated dsRNA sensor protects against severe COVID-19.

Wickenhagen Arthur A   Sugrue Elena E   Lytras Spyros S   Kuchi Srikeerthana S   Noerenberg Marko M   Turnbull Matthew L ML   Loney Colin C   Herder Vanessa V   Allan Jay J   Jarmson Innes I   Cameron-Ruiz Natalia N   Varjak Margus M   Pinto Rute M RM   Lee Jeffrey Y JY   Iselin Louisa L   Palmalux Natasha N   Stewart Douglas G DG   Swingler Simon S   Greenwood Edward J D EJD   Crozier Thomas W M TWM   Gu Quan Q   Davies Emma L EL   Clohisey Sara S   Wang Bo B   Trindade Maranhão Costa Fabio F   Freire Santana Monique M   de Lima Ferreira Luiz Carlos LC   Murphy Lee L   Fawkes Angie A   Meynert Alison A   Grimes Graeme G   Da Silva Filho Joao Luiz JL   Marti Matthias M   Hughes Joseph J   Stanton Richard J RJ   Wang Eddie C Y ECY   Ho Antonia A   Davis Ilan I   Jarrett Ruth F RF   Castello Alfredo A   Robertson David L DL   Semple Malcolm G MG   Openshaw Peter J M PJM   Palmarini Massimo M   Lehner Paul J PJ   Baillie J Kenneth JK   Rihn Suzannah J SJ   Wilson Sam J SJ  

Science (New York, N.Y.) 20211029 6567

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 respirator  ...[more]