IFITM3 restricts the morbidity and mortality associated with influenza

• Published in: Nature (London) Vol. 484; no. 7395; pp. 519 - 523
• Main Authors: Everitt, Aaron R., Clare, Simon, Pertel, Thomas, John, Sinu P., Wash, Rachael S., Smith, Sarah E., Chin, Christopher R., Feeley, Eric M., Sims, Jennifer S., Adams, David J., Wise, Helen M., Kane, Leanne, Goulding, David, Digard, Paul, Anttila, Verneri, Baillie, J. Kenneth, Walsh, Tim S., Hume, David A., Palotie, Aarno, Xue, Yali, Colonna, Vincenza, Tyler-Smith, Chris, Dunning, Jake, Gordon, Stephen B., Smyth, Rosalind L., Openshaw, Peter J., Dougan, Gordon, Brass, Abraham L., Kellam, Paul
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 26.04.2012; Nature Publishing Group
• Subjects: 631/326/596/2557; 631/45/612; 692/698/1543/1565; 692/699/255/1578; Alleles; Amino Acid Sequence; Analysis; Animals; Apoptosis; Avian flu; Biological and medical sciences; Blood; Complications and side effects; Cytokines - immunology; England - epidemiology; Gene Deletion; Genomes; Human viral diseases; Humanities and Social Sciences; Humans; Infectious diseases; Influenza; Influenza A virus - classification; Influenza A virus - growth & development; Influenza A virus - pathogenicity; 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 B virus - classification; Influenza B virus - growth & development; Influenza B virus - pathogenicity; Influenza, Human - complications; Influenza, Human - epidemiology; Influenza, Human - mortality; Influenza, Human - virology; letter; Leukocytes - immunology; Lung - pathology; Lung - virology; Lymphocytes; Medical sciences; Membrane proteins; Membrane Proteins - chemistry; Membrane Proteins - deficiency; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Sequence Data; Morbidity; Mortality; multidisciplinary; Orthomyxoviridae Infections - complications; Orthomyxoviridae Infections - mortality; Orthomyxoviridae Infections - pathology; Pandemics; Pathogens; Pathology; Patient outcomes; Physiological aspects; Pneumonia, Viral - etiology; Pneumonia, Viral - pathology; Pneumonia, Viral - prevention & control; Polymorphism, Single Nucleotide - genetics; Prevention; Risk factors; RNA-Binding Proteins - chemistry; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Science; Scotland - epidemiology; Swine influenza; United Kingdom; Viral diseases; Viral diseases of the respiratory system and ent viral diseases; Viral infections; Viral pneumonia; Virus Replication; Viruses; England; Scotland; United Kingdom; Orthomyxoviridae; Fulminant; Respiratory tract; Seasonal variation; Protection; Human; Viral pneumonia; Typing; H1N1 influenza; Mortality; Rodentia; Genotype; Hospitalization; In vitro; Morbidity; Infection; Virus; Pathogenicity; Resistance; In vivo; Vertebrata; Allele; Influenzavirus A; Mammalia; Mouse; Influenza A virus; Viral disease; Animal; Influenza; Replication; Interferon
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/nature10921

Interferon-inducible transmembrane (IFITM) protein 3 is shown to be an innate defence mechanism against viral infection in vivo ; furthermore, a subset of the patients hospitalized during the H1N1 2009 pandemic carried a variant form of the IFITM3 gene. Immune defence against flu virus Interferon-inducible transmembrane (IFITM) proteins restrict the replication of certain pathogenic viruses, but no in vivo role for these proteins has been known until now. Paul Kellam and colleagues now report that IFITM3 is essential for protecting mice infected with influenza viruses from developing fulminant viral pneumonia. The authors further find that a small subset of humans hospitalized for infection with pandemic H1N1/09 swine flu or seasonal influenza virus carried a variant of IFITM3 with reduced antiviral activity. These results suggest that IFITM3 has a pivotal role in defence against influenza infection. 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 1 , 2 , 3 , 4 , 5 , 6 , 7 . 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 8 , 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 9 , 10 . 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.