IFITM3 restricts the morbidity and mortality associated with influenza : Nature : Nature Publishing Group

IFITM3 restricts the morbidity and mortality associated with influenza : Nature : Nature Publishing Group

IFITM3 restricts the morbidity and mortality associated with influenza

• Aaron R. Everitt,


• Simon Clare,


• Thomas Pertel,


• Sinu P. John,


• Rachael S. Wash,


• Sarah E. Smith,


• Christopher R. Chin,


• Eric M. Feeley,


• Jennifer S. Sims,


• David J. Adams,


• Helen M. Wise,


• Leanne Kane,


• David Goulding,


• Paul Digard,


• Verneri Anttila,


• J. Kenneth Baillie,


• Tim S. Walsh,


• David A. Hume,


• Aarno Palotie,


• Yali Xue,


• Vincenza Colonna,


• Chris Tyler-Smith,


• Jake Dunning,


• Stephen B. Gordon,


• The GenISIS Investigators


• et al.

• Affiliations


• Contributions


• Corresponding authors

Nature

(2012)

doi:10.1038/nature10921

Received

07 September 2011

Accepted

08 February 2012

Published online

25 March 2012

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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, 2, 3, 4, 5, 6, 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 model⁸, 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.