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 XueVincenza Colonna, Chris Tyler-Smith, Jake Dunning, Stephen B. Gordon, Rosalind L. Smyth, Peter J. Openshaw, Gordon Dougan, Abraham L. Brass, Paul Kellam, K. Everingham, H. Dawson, D. Hope, P. Ramsay, A. Campbell, S. Kerr, D. Harrison, K. Rowan, J. Addison, N. Donald, S. Galt, D. Noble, J. Taylor, N. Webster, I. Taylor, J. Aldridge, R. Dornan, C. Richard, D. Gilmour, R. Simmons, R. White, C. Jardine, D. Williams, M. Booth, T. Quasim, V. Watson, P. Henry, F. Munro, L. Bell, J. Ruddy, S. Cole, J. Southward, P. Allcoat, S. Gray, M. McDougall, J. Matheson, J. Whiteside, D. Alcorn, K. Rooney, R. Sundaram, G. Imrie, J. Bruce, K. McGuigan, S. Moultrie, C. Cairns, J. Grant, M. Hughes, C. Murdoch, A. Davidson, G. Harris, R. Paterson, C. Wallis, S. Binning, M. Pollock, J. Antonelli, A. Duncan, J. Gibson, C. McCulloch, L. Murphy, C. Haley, G. Faulkner, T. Freeman, D. Chaussabel, W. E. Adamson, W. F. Carman, C. Thompson, M. C. Zambon, P. Aylin, D. Ashby, W. S. Barclay, S. J. Brett, W. O. Cookson, L. N. Drumright, R. A. Elderfield, L. Garcia-Alvarez, B. G. Gazzard, M. J. Griffiths, M. S. Habibi, T. T. Hansel, J. A. Herberg, A. H. Holmes, T. Hussell, S. L. Johnston, O. M. Kon, M. Levin, M. F. Moffatt, S. Nadel, J. O. Warner, S. J. Aston, A. Hay, J. McCauley, A. O'Garra, J. Banchereau, A. Hayward, P. Kellam, P. Simmonds, P. S. McNamara, M. G. Semple, J. S. Nguyen-Van-Tam, L. P. Ho, A. J. McMichael

Research output: Contribution to journalArticlepeer-review

550 Citations (Scopus)

Abstract

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. 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.

Original languageEnglish
Pages (from-to)519-523
Number of pages5
JournalNature
Volume484
Issue number7395
DOIs
Publication statusPublished - 26 Apr 2012

Bibliographical note

Funding Information:
This work was supported in part by the NSF, and by grant DC01797 from the NIH/NIDCD. We thank Jody Kreiman for many productive discussions. High speed imaging was done by Drs. Jody Kreiman and Bruce Gerratt.

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