title: IFITM3 restricts the morbidity and mortality associated with influenza.
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.
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK.
authors.forename: Aaron R
authors.initials: AR
authors.lastname: Everitt
authors.forename: Simon
authors.initials: S
authors.lastname: Clare
authors.forename: Thomas
authors.initials: T
authors.lastname: Pertel
authors.forename: Sinu P
authors.initials: SP
authors.lastname: John
authors.forename: Rachael S
authors.initials: RS
authors.lastname: Wash
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Smith
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Chin
authors.forename: Eric M
authors.initials: EM
authors.lastname: Feeley
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Sims
authors.forename: David J
authors.initials: DJ
authors.lastname: Adams
authors.forename: Helen M
authors.initials: HM
authors.lastname: Wise
authors.forename: Leanne
authors.initials: L
authors.lastname: Kane
authors.forename: David
authors.initials: D
authors.lastname: Goulding
authors.forename: Paul
authors.initials: P
authors.lastname: Digard
authors.forename: Verneri
authors.initials: V
authors.lastname: Anttila
authors.forename: J Kenneth
authors.initials: JK
authors.lastname: Baillie
authors.forename: Tim S
authors.initials: TS
authors.lastname: Walsh
authors.forename: David A
authors.initials: DA
authors.lastname: Hume
authors.forename: Aarno
authors.initials: A
authors.lastname: Palotie
authors.forename: Yali
authors.initials: Y
authors.lastname: Xue
authors.forename: Vincenza
authors.initials: V
authors.lastname: Colonna
authors.forename: Chris
authors.initials: C
authors.lastname: Tyler-Smith
authors.forename: Jake
authors.initials: J
authors.lastname: Dunning
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Gordon
authors.forename: Rosalind L
authors.initials: RL
authors.lastname: Smyth
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Openshaw
authors.forename: Gordon
authors.initials: G
authors.lastname: Dougan
authors.forename: Abraham L
authors.initials: AL
authors.lastname: Brass
authors.forename: Paul
authors.initials: P
authors.lastname: Kellam
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D016207:Cytokines / Q000276:immunology; D004739:England / Q000453:epidemiology; D017353:Gene Deletion; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000145:classification / Q000254:growth & development / Q000472:pathogenicity; D053122:Influenza A Virus, H3N2 Subtype / Q000145:classification / Q000254:growth & development / Q000472:pathogenicity; D009980:Influenza A virus / Q000145:classification / Q000254:growth & development / Q000472:pathogenicity*; D009981:Influenza B virus / Q000145:classification / Q000254:growth & development / Q000472:pathogenicity; D007251:Influenza, Human / Q000150:complications / Q000453:epidemiology / Q000401:mortality / Q000821:virology; D007962:Leukocytes / Q000276:immunology; D008168:Lung / Q000473:pathology / Q000821:virology; D008565:Membrane Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009976:Orthomyxoviridae Infections / Q000150:complications / Q000401:mortality* / Q000473:pathology; D011024:Pneumonia, Viral / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012606:Scotland / Q000453:epidemiology; D014779:Virus Replication
chemical_list: D016207:Cytokines; C080082:IFITM3 protein, human; D008565:Membrane Proteins; D016601:RNA-Binding Proteins; C462181:fragilis protein, mouse