A prenylated dsRNA sensor protects against severe COVID-19

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Wickenhagen, Arthur, Sugrue, Elena, Lytras, Spyros, Kuchi, Srikeerthana, Noerenberg, Marko, Turnbull, Matthew L, Loney, Colin, Herder, Vanessa, Allan, Jay, Jarmson, Innes et al (show 38 more authors) , Cameron-Ruiz, Natalia, Varjak, Margus, Pinto, Rute M, Lee, Jeffrey Y, Iselin, Louisa, Palmalux, Natasha, Stewart, Douglas G, Swingler, Simon, Greenwood, Edward JD, Crozier, Thomas WM, Gu, Quan, Davies, Emma L, Clohisey, Sara, Wang, Bo, Maranhao Costa, Fabio Trindade, Santana, Monique Freire, de Lima Ferreira, Luiz Carlos, Murphy, Lee, Fawkes, Angie, Meynert, Alison, Grimes, Graeme, Filho, Joao Luiz Da Silva, Marti, Matthias, Hughes, Joseph, Stanton, Richard J, Wang, Eddie CY, Ho, Antonia, Davis, Ilan, Jarrett, Ruth F, Castello, Alfredo, Robertson, David L, Semple, Malcolm G ORCID: 0000-0001-9700-0418, Openshaw, Peter JM, Palmarini, Massimo, Lehner, Paul J, Baillie, J Kenneth, Rihn, Suzannah J and Wilson, Sam J (2021) A prenylated dsRNA sensor protects against severe COVID-19. SCIENCE, 374 (6567). eabj3624-.

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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.

Item Type:	Article
Uncontrolled Keywords:	ISARIC4C Investigators, Animals, Chiroptera, Humans, Coronaviridae, Endoribonucleases, Phosphoric Diester Hydrolases, Isoenzymes, 2',5'-Oligoadenylate Synthetase, Interferons, Retroelements, RNA, Double-Stranded, 5' Untranslated Regions, RNA, Viral, Severity of Illness Index, Virus Replication, Polymorphism, Single Nucleotide, Protein Prenylation, A549 Cells, COVID-19, SARS-CoV-2
Divisions:	Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Infection, Veterinary and Ecological Sciences
Depositing User:	Symplectic Admin
Date Deposited:	01 Oct 2021 07:01
Last Modified:	18 Jan 2023 21:27
DOI:	10.1126/science.abj3624
Open Access URL:	https://doi.org/10.1126/science.abj3624
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3138818