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, The GenISIS Investigators, The MOSAIC Investigators, Rosalind L. Smyth, Peter J. Openshaw, Gordon Dougan, Abraham L. Brass & Paul Kellam
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 viruses1, 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 model8, 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’ influenza9, 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.
而关于IFITM3能抑制流感病毒也是本文作者Abraham L. Brass发现的，其研究发表在09年Cell上：The IFITM Proteins Mediate Cellular Resistance to Influenza A H1N1 Virus, West Nile Virus, and Dengue Virus。
作者: rojjer 时间: 2015-8-27 16:40
ipsvirus:
The IFITM Proteins Mediate Cellular Resistance to Influenza A H1N1 Virus, West Nile Virus, and Dengue Virus
Abraham L. Brass, I-Chueh Huang, Yair Benita, Sinu P. John, Manoj N. Krishnan, Eric M. Feeley, Bethany J. Ryan, Jessica L. Weyer, Louise van der Weyden, Erol Fikrig, David J. Adams, Ramnik J. Xavier, Michael Farzan, and Stephen J. Elledge
Influenza viruses exploit host cell machinery to replicate, resulting in epidemics of respiratory illness. In turn, the host expresses antiviral restriction factors to defend against infection. To find host cell modifiers of influenza A H1N1 viral infection, we used a functional genomic screen and identified over 120 influenza A virus-dependency factors with roles in endosomal acidification, vesicular trafficking, mitochondrial metabolism, and RNA splicing. We discovered that the interferon-inducible transmembrane proteins IFITM1, 2, and 3 restrict an early step in influenza A viral replication. The IFITM proteins confer basal resistance to influenza A virus but are also inducible by interferons type I and II and are critical for interferon's virustatic actions. Further characterization revealed that the IFITM proteins inhibit the early replication of flaviviruses, including dengue virus and West Nile virus. Collectively this work identifies a family of antiviral restriction factors that mediate cellular innate immunity to at least three major human pathogens.
