TY - JOUR
T1 - A prenylated dsRNA sensor protects against severe COVID-19
AU - Investigators, ISARIC4C
AU - Dark, Paul
N1 - Funding Information:
Thi work was partly funded by UKRI/NIHR through the UK Coronavirus Immunology Consortium (UK-CIC MR/V028448/1 to M.P. and S.J.W.) and the MRC through the following grants: MR/K024752/1 (to S.J.W.), MC_UU_12014/10 (to M.P. and S.J.W.), MC_UU_12014/12 (to J.H., D.L.R., and S.K.) and MR/P022642/1 (to S.J.W. and S.J.R.), MR/V000489/1 (to E.C.Y.W. and R.J.S.), MR/S00971X/1 (to R.J.S. and E.C.Y.W.), MR/P001602/1 (to E.C.Y.W.), and MR/V011561/1 (to P.J.L.). Support was also provided by a Wellcome Principal Research Fellowship 210688/Z/18/Z (to P.J.L.), a Wellcome Trust Fellowship 201366/Z/16/Z (to S.J.R.), a Wellcome Investigator Award 209412/Z/17/Z (to I.D.), the Addenbrooke's Charitable Trust and the NIHR Cambridge Biomedical Research Centre (to P.J.L.), support from the German Research Foundation, Deutsche Forschungsgemeinschaft; project number 406109949 (to V.H.), and German Federal Ministry of Food and Agriculture through BMEL F?rderkennzeichen: 01KI1723G (to V.H.), and a Daphne Jackson Fellowship funded by Medical Research Scotland (to S.S.). A.C. is supported by MRC grants MR/R021562/1, MC_UU_12014/10, and MC_UU_12014/12. J.Y.L. is funded by a Medial Sciences Graduate Studentship, University of Oxford. L.I. is funded by BBSRC DTP scholarship number BB/M011224/1. MAIC analysis was supported by the SHIELD Consortium (MRC grant MRNO2995X/1). ISARIC4C is supported by grants from the Medical Research Council (grant MC_PC_19059), the NIHR (award CO-CIN-01) and by the NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool in partnership with Public Health England (PHE), in collaboration with Liverpool School of Tropical Medicine and the University of Oxford (award 200907), NIHR HPRU in Respiratory Infections at Imperial College London with PHE (award 200927), Wellcome Trust and Department for International Development (215091/Z/18/Z), and the Bill and Melinda Gates Foundation (OPP1209135), and Liverpool Experimental Cancer Medicine Centre (C18616/A25153), NIHR Biomedical Research Centre at Imperial College London (IS-BRC-1215-20013), EU Platform foR European Preparedness Against (Re-)emerging Epidemics (PREPARE) (FP7 project 602525) and NIHR Clinical Research Network provided infrastructure support for this research.
Publisher Copyright:
Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).
PY - 2021/10/29
Y1 - 2021/10/29
N2 - 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.
AB - 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.
KW - 2',5'-Oligoadenylate Synthetase/genetics
KW - 5' Untranslated Regions
KW - A549 Cells
KW - Animals
KW - COVID-19/enzymology
KW - Chiroptera/genetics
KW - Coronaviridae/enzymology
KW - Endoribonucleases/metabolism
KW - Humans
KW - Interferons/immunology
KW - Isoenzymes/genetics
KW - Phosphoric Diester Hydrolases/genetics
KW - Polymorphism, Single Nucleotide
KW - Protein Prenylation
KW - RNA, Double-Stranded/chemistry
KW - RNA, Viral/chemistry
KW - Retroelements
KW - SARS-CoV-2/genetics
KW - Severity of Illness Index
KW - Virus Replication
UR - http://europepmc.org/abstract/med/34581622
U2 - 10.1126/science.abj3624
DO - 10.1126/science.abj3624
M3 - Article
C2 - 34581622
SN - 0036-8075
VL - 374
JO - Science (New York, N.Y.)
JF - Science (New York, N.Y.)
IS - 6567
M1 - eabj3624
ER -
