IFITM3 restricts the morbidity and mortality associated with influenza

被引:604
作者
Everitt, Aaron R. [1 ]
Clare, Simon [1 ]
Pertel, Thomas [2 ,3 ]
John, Sinu P. [2 ,3 ]
Wash, Rachael S. [1 ]
Smith, Sarah E. [1 ]
Chin, Christopher R. [2 ,3 ]
Feeley, Eric M. [2 ,3 ]
Sims, Jennifer S. [2 ,3 ]
Adams, David J. [1 ]
Wise, Helen M. [4 ]
Kane, Leanne [1 ]
Goulding, David [1 ]
Digard, Paul [4 ]
Anttila, Verneri [1 ]
Baillie, J. Kenneth [5 ,6 ]
Walsh, Tim S. [6 ]
Hume, David A. [5 ]
Palotie, Aarno [1 ]
Xue, Yali [1 ]
Colonna, Vincenza [1 ,7 ]
Tyler-Smith, Chris [1 ]
Dunning, Jake [8 ]
Gordon, Stephen B. [9 ]
Smyth, Rosalind L. [10 ]
Openshaw, Peter J. [8 ]
Dougan, Gordon [1 ]
Brass, Abraham L. [2 ,3 ,11 ]
Kellam, Paul [1 ,12 ]
机构
[1] Wellcome Trust Sanger Inst, Hinxton CB10 1SA, England
[2] MIT, Ragon Inst Massachusetts, Gen Hosp, Charlestown, MA 02129 USA
[3] Harvard Univ, Charlestown, MA 02129 USA
[4] Univ Cambridge, Dept Pathol, Div Virol, Cambridge CB2 1QP, England
[5] Univ Edinburgh, Div Genet & Genom, Roslin Inst, Roslin EH25 9RG, Midlothian, Scotland
[6] Univ Edinburgh, Dept Crit Care Med, Edinburgh EH16 4TJ, Midlothian, Scotland
[7] Natl Res Council CNR, Inst Genet & Biophys A Buzzati Traverso, Naples, Italy
[8] Univ London Imperial Coll Sci Technol & Med, Ctr Resp Infect, Natl Heart & Lung Inst, London W2 1PG, England
[9] Univ Liverpool, Liverpool Sch Trop Med, Liverpool L3 5QA, Merseyside, England
[10] Univ Liverpool, Inst Translat Med, Alder Hey Childrens Hosp, Liverpool L12 2AP, Merseyside, England
[11] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02117 USA
[12] UCL, UCL MRC Ctr Med Mol Virol, Dept Infect, London W1T 4JF, England
基金
英国惠康基金; 英国生物技术与生命科学研究理事会; 英国医学研究理事会;
关键词
WEST NILE VIRUS; PROTEINS; PATHOGENESIS; INFECTION;
D O I
10.1038/nature10921
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The 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(1-7). 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(8), 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(9,10). 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.
引用
收藏
页码:519 / U146
页数:7
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