1. IFITM3 restricts the morbidity and mortality associated with influenza.
- Author
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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, Smyth RL, Openshaw PJ, Dougan G, Brass AL, and Kellam P
- Subjects
- Alleles, Amino Acid Sequence, Animals, Cytokines immunology, England epidemiology, Gene Deletion, Humans, Influenza A Virus, H1N1 Subtype classification, Influenza A Virus, H1N1 Subtype growth & development, Influenza A Virus, H1N1 Subtype pathogenicity, Influenza A Virus, H3N2 Subtype classification, Influenza A Virus, H3N2 Subtype growth & development, Influenza A Virus, H3N2 Subtype pathogenicity, Influenza A virus classification, Influenza A virus growth & development, Influenza B virus classification, Influenza B virus growth & development, Influenza B virus pathogenicity, Influenza, Human complications, Influenza, Human epidemiology, Influenza, Human mortality, Influenza, Human virology, Leukocytes immunology, Lung pathology, Lung virology, Membrane Proteins chemistry, Membrane Proteins deficiency, Membrane Proteins genetics, Mice, Mice, Inbred C57BL, Mice, Knockout, Molecular Sequence Data, Orthomyxoviridae Infections complications, Orthomyxoviridae Infections pathology, Pneumonia, Viral etiology, Pneumonia, Viral pathology, Pneumonia, Viral prevention & control, Polymorphism, Single Nucleotide genetics, RNA-Binding Proteins chemistry, RNA-Binding Proteins genetics, Scotland epidemiology, Virus Replication, Influenza A virus pathogenicity, Membrane Proteins metabolism, Orthomyxoviridae Infections mortality, RNA-Binding Proteins metabolism
- 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.
- Published
- 2012
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