Nature. 2012 Mar 25. doi: 10.1038/nature10921. [Epub ahead of print]
IFITM3 restricts the morbidity and mortality associated with influenza.
Everitt AR, Clare S, Pertel T, John SP, Wash RS, Smith SE, Chin CR, Feeley EM, Sims JS, Adams DJ, Wise HM, Kane L, Goulding D, Digard P, Anttila V, Baillie JK, Walsh TS, Hume DA, Palotie A, Xue Y, Colonna V, Tyler-Smith C, Dunning J, Gordon SB; The GenISIS Investigators; Critical Care Medicine, University of Edinburgh, Everingham K, Dawson H, Hope D, Ramsay P, Walsh Local Lead Investigator TS; Generation Scotland, University of Edinburgh Molecular Medicine Centre, Campbell A, Kerr S; Intensive Care National Audit & Research Centre, London, Harrison D, Rowan K; Intensive Care Unit, Aberdeen Royal Infirmary, Addison J, Donald N, Galt S, Noble D, Taylor J, Webster Local Lead Investigator N; Intensive Care Unit, Ayr Hospital, Taylor Local Lead Investigator I; Intensive Care Unit, Borders General Hospital, Melrose, Aldridge Local Lead Investigator J, Dornan R, Richard C; Intensive Care Unit, Crosshouse Hospital, Kilmarnock, Gilmour D, Simmons Local Lead Investigator R, White Local Lead Investigator R; Intensive Care Unit, Dumfries and Galloway Royal Infirmary, Jardine C, Williams Local Lead Investigator D; Intensive Care Unit, Glasgow Royal Infirmary, Booth Local Lead Investigator M, Quasim T; Intensive Care Unit, Hairmyres Hospital, Lanarkshire, Watson V; Intensive Care Unit, Inverclyde Royal Hospital, Greenock, Henry P, Munro F; Intensive Care Unit, Monklands Hospital, Airdrie, Bell L, Ruddy Local Lead Investigator J; Intensive Care Unit, Ninewells Hospital, Dundee, Cole Local Lead Investigator S, Southward J; Intensive Care Unit, Queen Margaret Hospital, Dunfermline, Allcoat P, Gray S, McDougall Local Lead Investigator M; Intensive Care Unit, Raigmore Hospital, Inverness, Matheson J, Whiteside Local Lead Investigator J; Intensive Care Unit, Royal Alexandra Hospital, Paisley, Alcorn D, Rooney Local Lead Investigator K, Sundaram R; Intensive Care Unit, Southern General Hospital, Glasgow, Imrie Local Lead Investigator G; Intensive Care Unit, St John’s Hospital, Livingston, Bruce J, McGuigan K, Moultrie Local Lead Investigator S; Intensive Care Unit, Stirling Royal Infirmary, Cairns Local Lead Investigator C, Grant J, Hughes M; Intensive Care Unit, Stobhill Hospital, Glasgow, Murdoch Local Lead Investigator C; Intensive Care Unit, Victoria Hospital, Glasgow, Davidson Local Lead Investigator A; Intensive Care Unit, Western General Hospital, Edinburgh, Harris G, Paterson R, Wallis Local Lead Investigator C; Intensive Care Unit, Western Infirmary, Glasgow, Binning Local Lead Investigator S, Pollock M; Wellcome Trust Clinical Research Facility, Edinburgh, Antonelli J, Duncan A, Gibson J, McCulloch C, Murphy L; Roslin Institute, University of Edinburgh, Haley C, Faulkner G, Freeman T, Hume DA, Baillie Principal Investigator JK; The MOSAIC Investigators; Benaroya Research Institute, USA, Chaussabel D; Gartnavel General Hospital, Greater Glasgow, UK, Adamson WE, Carman WF; Health Protection Agency, UK, Thompson C, Zambon MC; Imperial College London, UK, Aylin P, Ashby D, Barclay WS, Brett SJ, Cookson WO, Drumright LN, Dunning J, Elderfield RA, Garcia-Alvarez L, Gazzard BG, Griffiths MJ, Habibi MS, Hansel TT, Herberg JA, Holmes AH, Hussell T, Johnston SL, Kon OM, Levin M, Moffatt MF, Nadel S, Openshaw PJ, Warner JO; Liverpool School of Tropical Medicine, UK, Aston SJ, Gordon SB; National Institute for Medical Research, UK, Hay A, McCauley J, O'Garra A; Roche, Nutley, USA, Banchereau J; University College London, UK, Hayward A, Kellam P; University of Edinburgh, UK, Baillie JK, Hume DA, Simmonds P; University of Liverpool, UK, McNamara PS, Semple MG, Smyth RL; University of Nottingham, UK, Nguyen-Van-Tam JS; University of Oxford, UK, Ho LP, McMichael AJ; Wellcome Trust Sanger Institute, UK, Kellam P, Smyth RL, Openshaw PJ, Dougan G, Brass AL, Kellam P.
SourceWellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK.
AbstractThe 2009 H1N1 influenza pandemic showed the speed with which a novel respiratory virus can spread and the ability of a generally mild infection to induce severe morbidity and mortality in a subset of the population. Recent in vitro studies show that the interferon-inducible transmembrane (IFITM) protein family members potently restrict the replication of multiple pathogenic viruses. Both the magnitude and breadth of the IFITM proteins' in vitro effects suggest that they are critical for intrinsic resistance to such viruses, including influenza viruses. Using a knockout mouse model, we now test this hypothesis directly and find that IFITM3 is essential for defending the host against influenza A virus in vivo. Mice lacking Ifitm3 display fulminant viral pneumonia when challenged with a normally low-pathogenicity influenza virus, mirroring the destruction inflicted by the highly pathogenic 1918 'Spanish' influenza. Similar increased viral replication is seen in vitro, with protection rescued by the re-introduction of Ifitm3. To test the role of IFITM3 in human influenza virus infection, we assessed the IFITM3 alleles of individuals hospitalized with seasonal or pandemic influenza H1N1/09 viruses. We find that a statistically significant number of hospitalized subjects show enrichment for a minor IFITM3 allele (SNP rs12252-C) that alters a splice acceptor site, and functional assays show the minor CC genotype IFITM3 has reduced influenza virus restriction in vitro. Together these data reveal that the action of a single intrinsic immune effector, IFITM3, profoundly alters the course of influenza virus infection in mouse and humans.
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