A prenylated dsRNA sensor protects against severe COVID-19

Science. 2021 Oct 29;374(6567):eabj3624. doi: 10.1126/science.abj3624.

Arthur Wickenhagen ¹, Elena Sugrue ^# ¹, Spyros Lytras ^# ¹, Srikeerthana Kuchi ^# ¹, Marko Noerenberg ^# ¹, Matthew L Turnbull ^# ¹, Colin Loney ¹, Vanessa Herder ¹, Jay Allan ¹, Innes Jarmson ¹, Natalia Cameron-Ruiz ¹, Margus Varjak ¹, Rute M Pinto ¹, Jeffrey Y Lee ², Louisa Iselin ¹ ² ³, Natasha Palmalux ¹, Douglas G Stewart ¹, Simon Swingler ¹, Edward J D Greenwood ⁴, Thomas W M Crozier ⁴, Quan Gu ¹, Emma L Davies ¹, Sara Clohisey ⁵, Bo Wang ⁵, Fabio Trindade Maranhão Costa ⁶, Monique Freire Santana ⁷, Luiz Carlos de Lima Ferreira ⁸, Lee Murphy ⁹, Angie Fawkes ⁹, Alison Meynert ¹⁰, Graeme Grimes ¹⁰, ISARIC4C Investigators, Joao Luiz Da Silva Filho ¹¹, Matthias Marti ¹¹, Joseph Hughes ¹, Richard J Stanton ¹², Eddie C Y Wang ¹², Antonia Ho ¹, Ilan Davis ², Ruth F Jarrett ¹, Alfredo Castello ¹, David L Robertson ¹, Malcolm G Semple ¹³ ¹⁴, Peter J M Openshaw ¹⁵ ¹⁶, Massimo Palmarini ¹, Paul J Lehner ⁴, J Kenneth Baillie ⁵ ¹⁰ ¹⁷, Suzannah J Rihn ¹, Sam J Wilson ¹

Affiliations

1 Medical Research Council-University of Glasgow Centre for Virus Research (CVR), Institute of Infection, Inflammation and Immunity, University of Glasgow, Glasgow, UK.
2 Department of Biochemistry, University of Oxford, Oxford, UK.
3 Nuffield Department of Medicine, University of Oxford, Oxford, UK.
4 Cambridge Institute of Therapeutic Immunology and Infectious Disease, University of Cambridge, Cambridge, UK.
5 Roslin Institute, University of Edinburgh, Edinburgh, UK.
6 Laboratory of Tropical Diseases, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Sao Paolo, Brazil.
7 Department of Education and Research, Oncology Control Centre of Amazonas State (FCECON), Manaus, Amazonas, Brazil.
8 Postgraduate Program in Tropical Medicine, Tropical Medicine Foundation Dr. Heitor Vieira Dourado, Manaus, Amazonas, Brazil.
9 Edinburgh Clinical Research Facility, University of Edinburgh, Western General Hospital, Edinburgh, UK.
10 Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK.
11 Wellcome Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK.
12 Division of Infection & Immunity, Cardiff University, Cardiff, UK.
13 NIHR Health Protection Research Unit for Emerging and Zoonotic Infections, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK.
14 Respiratory Medicine, Alder Hey Children's Hospital, Liverpool, UK.
15 National Heart and Lung Institute, Imperial College London, London, UK.
16 Imperial College Healthcare, National Health Service Trust London, London, UK.
17 Intensive Care Unit, Royal Infirmary of Edinburgh, Edinburgh, UK.
# Contributed equally.

PMID: 34581622 DOI: 10.1126/science.abj3624

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.

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