IFITM3 restricts the morbidity and mortality associated with influenza

Abstract

Background: 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 an unfortunate few. 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 they are critical for intrinsic resistance to such viruses, including influenza viruses. Methods: Using a knockout mouse as a model of influenza virus infection we directly tested this hypothesis and found that IFITM3 is essential for defending the host against influenza A virus in vivo. We also tested the role of IFITM3 in human influenza virus infection by assessing the IFITM3 alleles of individuals hospitalised with seasonal or pandemic influenza H1N1/09 viruses. Results: 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. We also found that a statistically significant number of hospitalised subjects show enrichment for a minor IFITM3 single nucleotide polymorphism that alters a splice acceptor site, and functional assays showed the minor CC genotype IFITM3 has reduced influenza virus restriction in vitro. Conclusion: Our data reveals that the action of a single intrinsic immune effector, IFITM3, profoundly alters the course of influenza virus infection in mouse and man.