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2 results on '"Silva-Filho JL"'

1. A prenylated dsRNA sensor protects against severe COVID-19.

Author

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, and Wilson SJ

Subjects
5' Untranslated Regions, A549 Cells, Animals, COVID-19 enzymology, COVID-19 immunology, Chiroptera genetics, Chiroptera virology, Coronaviridae enzymology, Coronaviridae genetics, Coronaviridae physiology, Endoribonucleases metabolism, Humans, Interferons immunology, Isoenzymes genetics, Isoenzymes metabolism, Phosphoric Diester Hydrolases genetics, Phosphoric Diester Hydrolases metabolism, Polymorphism, Single Nucleotide, Protein Prenylation, RNA, Double-Stranded chemistry, RNA, Double-Stranded genetics, RNA, Viral chemistry, RNA, Viral genetics, Retroelements, SARS-CoV-2 genetics, Severity of Illness Index, Virus Replication, 2',5'-Oligoadenylate Synthetase genetics, 2',5'-Oligoadenylate Synthetase metabolism, COVID-19 genetics, COVID-19 physiopathology, RNA, Double-Stranded metabolism, RNA, Viral metabolism, SARS-CoV-2 physiology
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.

Published
2021
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2. A prenylated dsRNA sensor protects against severe COVID-19

Author

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, 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, Paxton, WA, Pollakis, G, Price, N, Rambaut, A, 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, 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, Wham, M, 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, 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, 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, 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, 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, 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, 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, Winchester, S, Wiselka, M, Wolverson, A, Wootton, DG, Workman, A, Yates, B, Young, P, Division of Computational and Systems Medicine, Imperial College London, London, SW7 2AZ, UK, Imperial College London - National Heart and Lung Institute, Centre National de la Recherche Scientifique (CNRS), MRC - University of Glasgow Centre for Virus Research, University of Kent [Canterbury], University of Glasgow, National Institute for Health Research, UK Research and Innovation, UKRI MRC COVID-19 Rapid Response Call, Mentzer, AJ, Investigators, ISARIC4C, Lee, J, and Angus, B

Subjects
2',5'-Oligoadenylate Synthetase/genetics, L PATHWAY, viruses, SINGLE-NUCLEOTIDE POLYMORPHISM, RNASE-L, RNA, Viral/chemistry, RNA, Double-Stranded/chemistry, Virus Replication, Severity of Illness Index, COVID-19/enzymology, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Chiroptera, Sense (molecular biology), 2',5'-Oligoadenylate Synthetase, MESH: COVID-19, MESH: Animals, MESH: Interferons, ENZYME-ACTIVITY, MESH: 2',5'-Oligoadenylate Synthetase, Endoribonucleases/metabolism, 0303 health sciences, MESH: Protein Prenylation, Multidisciplinary, I INTERFERON, Coronaviridae/enzymology, MESH: Polymorphism, Single Nucleotide, 030302 biochemistry & molecular biology, MESH: Chiroptera, CORONAVIRUS REPLICATION, 3. Good health, Cell biology, Multidisciplinary Sciences, Isoenzymes, RNA silencing, VIRUS NS1 PROTEIN, MESH: RNA, Viral, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, MESH: Isoenzymes, Science & Technology - Other Topics, RNA, Viral, MESH: 5' Untranslated Regions, [SDV.IMM]Life Sciences [q-bio]/Immunology, SARS-CORONAVIRUS, Gene isoform, MESH: Endoribonucleases, Retroelements, RNase P, Coronaviridae, General Science & Technology, Protein Prenylation, Biology, Polymorphism, Single Nucleotide, Chiroptera/genetics, 03 medical and health sciences, MESH: RNA, Double-Stranded, MESH: Retroelements, SARS-CoV-2/genetics, MESH: Severity of Illness Index, Endoribonucleases, Animals, Humans, MESH: SARS-CoV-2, Interferons/immunology, Gene, ISARIC4C Investigators, 030304 developmental biology, RNA, Double-Stranded, Science & Technology, MESH: Humans, ACCEPTOR SITE, Phosphoric Diester Hydrolases, SARS-CoV-2, fungi, MESH: Virus Replication, RNA, COVID-19, Phosphoric Diester Hydrolases/genetics, Viral replication, A549 Cells, Protein prenylation, SPLICE-SITE POLYMORPHISM, Interferons, MESH: A549 Cells, 5' Untranslated Regions, MESH: Phosphoric Diester Hydrolases, Isoenzymes/genetics, MESH: Coronaviridae
Abstract

International audience; INTRODUCTIONInterferons (IFNs) are cytokines that are rapidly deployed in response to invading pathogens. By initiating a signaling cascade that stimulates the expression of hundreds of genes, IFNs create an antiviral state in host cells. Because IFNs heavily influence COVID-19 outcomes, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication can be inhibited by the antiviral state, it is important to understand how the individual antiviral effectors encoded by IFN-stimulated genes (ISGs) inhibit SARS-CoV-2.RATIONALEWe hypothesized that IFN-stimulated antiviral effectors can inhibit SARS-CoV-2, and that variation at the loci encoding these defenses underlies why some people are more susceptible to severe COVID-19.RESULTSWe used arrayed ISG expression screening to reveal that 2′-5′-oligoadenylate synthetase 1 (OAS1) consistently inhibited SARS-CoV-2 in different contexts. Using CRISPR-Cas9, we found that endogenous OAS1 makes a substantial contribution to the antiviral state by recognizing short stretches of double-stranded RNA (dsRNA) and activating RNase L. We globally mapped where OAS1 binds to SARS-CoV-2 viral RNAs and found that OAS1 binding is remarkably specific, with two conserved stem loops in the SARS-CoV-2 5′-untranslated region (UTR) constituting the principal viral target.OAS1 expression was readily detectable at the sites of infection in individuals who died of COVID-19, and specific OAS1 alleles are known to be associated with altered susceptibility to infection and severe disease. It had previously been reported that alleles containing a common splice-acceptor single nucleotide polymorphism in OAS1 (Rs10774671) were associated with less severe COVID-19. We determined that people with at least one allele with a G at this position could express a prenylated form of OAS1 (p46), whereas other individuals could not. Using a series of mutants, we found that C-terminal prenylation was necessary for OAS1 to initiate a block to SARS-CoV-2. Furthermore, confocal microscopy revealed that prenylation targeted OAS1 to perinuclear structures rich in viral dsRNA, whereas non-prenylated OAS1 was diffusely localized and unable to initiate a detectable block to SARS-CoV-2 replication.The realization that prenylation is essential for OAS1-mediated sensing of SARS-CoV-2 allowed us to examine the transcriptome of infected patients and investigate whether there was a link between the expression of prenylated OAS1 and SARS-CoV-2 disease progression. Analysis of the OAS1 transcripts from 499 hospitalized COVID-19 patients revealed that expressing prenylated OAS1 was associated with protection from severe COVID-19.Because prenylated OAS1 was so important in human cases, we wanted to determine whether horseshoe bats, the likely source of SARS-CoV-2, possessed the same defense. When we examined the genomic region where the prenylation signal should reside, retrotransposition of a long terminal repeat sequence had ablated this signal, preventing the expression of prenylated anti-CoV OAS1 in these bats.CONCLUSIONC-terminal prenylation targets OAS1 to intracellular sites rich in viral dsRNA, which are likely the SARS-CoV-2 replicative organelles. Once in the right place, OAS1 binds to dsRNA structures in the SARS-CoV-2 5′-UTR and initiates a potent block to SARS-CoV-2 replication. Thus, the correct targeting of OAS1 and the subsequent inhibition of SARS-CoV-2 likely underpins the genetic association of alleles containing a G at Rs10774671 with reduced susceptibility to infection and severe disease in COVID-19. Moreover, the conspicuous absence of this antiviral defense in horseshoe bats potentially explains why SARS-CoV-2 is so sensitive to this defense in humans.

Published
2021

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