A prenylated dsRNA sensor protects against severe COVID-19.
Wickenhagen A., Sugrue E., Lytras S., Kuchi S., Noerenberg M., Turnbull ML., Loney C., Herder V., Allan J., Jarmson I., Cameron-Ruiz N., Varjak M., Pinto RM., Lee JY., Iselin L., Palmalux N., Stewart DG., Swingler S., Greenwood EJD., Crozier TWM., Gu Q., Davies EL., Clohisey S., Wang B., Trindade Maranhão Costa F., Freire Santana M., de Lima Ferreira LC., Murphy L., Fawkes A., Meynert A., Grimes G., ISARIC4C Investigators None., Da Silva Filho JL., Marti M., Hughes J., Stanton RJ., Wang ECY., Ho A., Davis I., Jarrett RF., Castello A., Robertson DL., Semple MG., Openshaw PJM., Palmarini M., Lehner PJ., Baillie JK., Rihn SJ., Wilson SJ.
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.