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Norway

PMID:22446628  

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 | GenISIS Investigators | MOSAIC Investigators | Rosalind L Smyth | Peter J Openshaw | Gordon Dougan | Abraham L Brass | Paul Kellam
Nature | 2012

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.

Pubmed ID: 22446628

Research resources used in this publication

None found

Antibodies used in this publication

None found

Associated grants

  • Agency: Wellcome Trust, United Kingdom
    Id: 090385/Z/09/Z
  • Agency: NIDDK NIH HHS, United States
    Id: P30 DK043351
  • Agency: Medical Research Council, United Kingdom
    Id: G0901697
  • Agency: Medical Research Council, United Kingdom
    Id: G0800777
  • Agency: Department of Health, United Kingdom
    Id: DHCS/04/G121/68
  • Agency: NIAID NIH HHS, United States
    Id: R01 AI091786
  • Agency: Wellcome Trust, United Kingdom
    Id: 098051
  • Agency: Medical Research Council, United Kingdom
    Id: G0802752
  • Agency: Medical Research Council, United Kingdom
    Id: G0600511
  • Agency: NIAID NIH HHS, United States
    Id: R01AI091786
  • Agency: Medical Research Council, United Kingdom
    Id: G0800767
  • Agency: Wellcome Trust, United Kingdom
    Id: 090382
  • Agency: Medical Research Council, United Kingdom
    Id: G1000758
  • Agency: Medical Research Council, United Kingdom
    Id: MC_U122785833
  • Agency: Wellcome Trust, United Kingdom
    Id: 090382/Z/09/Z
  • Agency: Medical Research Council, United Kingdom
    Id: G0600371
  • Agency: Chief Scientist Office, United Kingdom
  • Agency: Cancer Research UK, United Kingdom
    Id: 13031
  • Agency: Medical Research Council, United Kingdom
    Id: MC_G1001212

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