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 OAS1, through RNase L, potently inhibits SARS-CoV-2. We show that a common splice-acceptor SNP (Rs10774671) governs whether people express prenylated OAS1 isoforms that are membrane-associated and sense specific regions of SARS-CoV-2 RNAs, or only express cytosolic, nonprenylated OAS1 that does not efficiently detect SARS-CoV-2. Importantly, in hospitalized patients, expression of prenylated OAS1 was associated with protection from severe COVID-19, suggesting this antiviral defense is a major component of a protective antiviral response.

Metadata

Authors/Creators:	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 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 ISARIC4C Investigators Baillie, JK Semple, MG Openshaw, PJM Carson, G Alex, B Bach, B Barclay, WS Bogaert, D Chand, M Cooke, GS Docherty, AB Dunning, J da Silva Filipe, A Fletcher, T Green, CA Harrison, EM Ho, AYW Horby, PW Ijaz, S Khoo, S Klenerman, P Law, A Lim, WS Mentzer, AJ Merson, L Meynert, AM Noursadeghi, M Moore, SC Palmarini, M Paxton, WA Pollakis, G Price, N Rambaut, A Robertson, DL Russell, CD Sancho-Shimizu, V Scott, JT de Silva, T Sigfrid, L Solomon, T Sriskandan, S Stuart, D Summers, C Tedder, RS Thomson, EC Thompson, AAR https://orcid.org/0000-0002-0717-4551 Thwaites, RS Turtle, LCW Gupta, RK Palmieri, C Swann, OV Zambon, M Dumas, M-E Griffin, JL Takats, Z Chechi, K Andrikopoulos, P Osagie, A Olanipekun, M Liggi, S Lewis, MR Dos Santos Correia, G Sands, CJ Takis, P Maslen, L Hardwick, H Donohue, C Griffiths, F Oosthuyzen, W Donegan, C Spencer, RG Norman, L Pius, R Drake, TM Fairfield, CJ Knight, SR Mclean, KA Murphy, D Shaw, CA Dalton, J Girvan, M Saviciute, E Roberts, S Harrison, J Marsh, L Connor, M Halpin, S Jackson, C Gamble, C Plotkin, D Lee, J Leeming, G Law, A Wham, M Clohisey, S Hendry, R Scott-Brown, J Greenhalf, W Shaw, V McDonald, SE Keating, S Ahmed, KA Armstrong, JA Ashworth, M Asiimwe, IG Bakshi, S Barlow, SL Booth, L Brennan, B Bullock, K Catterall, BWA Clark, JJ Clarke, EA Cole, S Cooper, L Cox, H Davis, C Dincarslan, O Dunn, C Dyer, P Elliott, A Evans, A Finch, L Fisher, LWS Foster, T Garcia-Dorival, I Greenhalf, W Gunning, P Hartley, C Jensen, RL Jones, CB Jones, TR Khandaker, S King, K Kiy, RT Koukorava, C Lake, A Lant, S Latawiec, D Lavelle-Langham, L Lefteri, D Lett, L Livoti, LA Mancini, M McDonald, S McEvoy, L McLauchlan, J Metelmann, S Miah, NS Middleton, J Mitchell, J Moore, SC Murphy, EG Penrice-Randal, R Pilgrim, J Prince, T Reynolds, W Ridley, PM Sales, D Shaw, VE Shears, RK Small, B Subramaniam, KS Szemiel, A Taggart, A Tanianis-Hughes, J Thomas, J Trochu, E van Tonder, L Wilcock, E Zhang, JE Flaherty, L Maziere, N Cass, E Carracedo, AD Carlucci, N Holmes, A Massey, H Murphy, L Wrobel, N McCafferty, S Morrice, K MacLean, A Adeniji, K Agranoff, D Agwuh, K Ail, D Aldera, EL Alegria, A Allen, S Angus, B Ashish, A Atkinson, D Bari, S Barlow, G Barnass, S Barrett, N Bassford, C Basude, S Baxter, D Beadsworth, M Bernatoniene, J Berridge, J Berry, C Best, N Bothma, P Chadwick, D Brittain-Long, R Bulteel, N Burden, T Burtenshaw, A Caruth, V Chadwick, D Chambler, D Chee, N Child, J Chukkambotla, S Clark, T Collini, P Cosgrove, C Cupitt, J Cutino-Moguel, M-T Dark, P Dawson, C Dervisevic, S Donnison, P Douthwaite, S Drummond, A DuRand, I Dushianthan, A Dyer, T Evans, C Eziefula, C Fegan, C Finn, A Fullerton, D Garg, S Garg, A Gkrania-Klotsas, E Godden, J Goldsmith, A Graham, C Hardy, E Hartshorn, S Harvey, D Havalda, P Hawcutt, DB Hobrok, M Hodgson, L Hormis, A Jacobs, M Jain, S Jennings, P Kaliappan, A Kasipandian, V Kegg, S Kelsey, M Kendall, J Kerrison, C Kerslake, I Koch, O Koduri, G Koshy, G Laha, S Laird, S Larkin, S Leiner, T Lillie, P Limb, J Linnett, V Little, J Lyttle, M MacMahon, M MacNaughton, E Mankregod, R Masson, H Matovu, E McCullough, K McEwen, R Meda, M Mills, G Minton, J Mirfenderesky, M Mohandas, K Mok, Q Moon, J Moore, E Morgan, P Morris, C Mortimore, K Moses, S Mpenge, M Mulla, R Murphy, M Nagel, M Nagarajan, T Nelson, M Norris, L O'Shea, MK Otahal, I Ostermann, M Pais, M Palmieri, C Panchatsharam, S Papakonstantinou, D Paraiso, H Patel, B Pattison, N Pepperell, J Peters, M Phull, M Pintus, S Singh Pooni, J Planche, T Post, F Price, D Prout, R Rae, N Reschreiter, H Reynolds, T Richardson, N Roberts, M Roberts, D Rose, A Rousseau, G Ruge, B Ryan, B Saluja, T Schmid, ML Shah, A Shanmuga, P Sharma, A Shawcross, A Sizer, J Shankar-Hari, M Smith, R Snelson, C Spittle, N Staines, N Stambach, T Stewart, R Subudhi, P Szakmany, T Tatham, K Thomas, J Thompson, C Thompson, R Tridente, A Tupper-Carey, D Twagira, M Vallotton, N Vancheeswaran, R Vincent-Smith, L Visuvanathan, S Vuylsteke, A Waddy, S Wake, R Walden, A Welters, I Whitehouse, T Whittaker, P Whittington, A Papineni, P Wijesinghe, M Williams, M Wilson, L Cole, S Winchester, S Wiselka, M Wolverson, A Wootton, DG Workman, A Yates, B Young, P
Copyright, Publisher and Additional Information:	© 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). https://creativecommons.org/licenses/by/4.0/. This is an open-access article distributed under the terms of the Creative Commons Attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Dates:	Accepted: 23 September 2021 Published (online): 28 September 2021 Published: 29 October 2021
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Sheffield Teaching Hospitals
Depositing User:	Symplectic Sheffield
Date Deposited:	11 Oct 2021 08:01
Last Modified:	09 Mar 2022 17:27
Status:	Published
Publisher:	American Association for the Advancement of Science
Refereed:	Yes
Identification Number:	https://doi.org/10.1126/science.abj3624
Related URLs:	PubMed URL

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A prenylated dsRNA sensor protects against severe COVID-19

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