Cell. The IFITM Proteins Mediate Cellular Resistance to Influenza A H1N1 Virus, West Nile Virus, and Dengue Virus

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The IFITM Proteins Mediate Cellular Resistance to Influenza A H1N1 Virus, West Nile Virus, and Dengue Virus (Cell, abstract, edited)

[Source Full Free PDF Document: LINK. EDITED.]

The IFITM Proteins Mediate Cellular Resistance to Influenza A H1N1 Virus, West Nile Virus, and Dengue Virus

Abraham L. Brass,1,2,4,9,* I-Chueh Huang,5,9 Yair Benita,3,10 Sinu P. John,1,10 Manoj N. Krishnan,6 Eric M. Feeley,1 Bethany J. Ryan,1 Jessica L. Weyer,5 Louise van der Weyden,8 Erol Fikrig,6,7 David J. Adams,8 Ramnik J. Xavier,2,3 Michael Farzan,5,* and Stephen J. Elledge4,*

1Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard Medical School, Charlestown, MA 02129, USA
2Gastrointestinal Unit
3Center for Computational and Integrative Biology Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
4Department of Genetics, Harvard Medical School, Division of Genetics, Brigham and Women?s Hospital, Howard Hughes Medical Institute, Boston, MA 02115, USA
5Department of Microbiology and Molecular Genetics, Harvard Medical School, New England Primate Research Center, Southborough, MA 01772, USA
6Section of Infectious Diseases, Department of Internal Medicine
7Howard Hughes Medical Institute Yale University School of Medicine, New Haven, CT 06520, USA
8Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton Cambridge CB10 1SA, UK
9These authors contributed equally to this work
10These authors contributed equally to this work

*Correspondence: abrass@partners.org (A.L.B.), farzan@hms.harvard.edu (M.F.), selledge@genetics.med.harvard.edu (S.J.E.)

DOI 10.1016/j.cell.2009.12.017


SUMMARY

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 immunityto at least three
major human pathogens.

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Re: Cell. The IFITM Proteins Mediate Cellular Resistance to Influenza A H1N1 Virus, West Nile Virus, and Dengue Virus

I thought these pics from the study were worth posting.



Figure 2. Integrated Model of Influenza A Virus Host Factors
Using the influenza A virus life cycle as a guide (Lamb and Krug, 2001), the candidate proteins from the human and fly screens were placed at the position most likely to be relevant to the virus using a database of annotations from Gene Ontology, KEGG, Reactome, and OMIM (see Experimental Procedures). Computational mapping and supporting evidences were reviewed and refined manually (Datasets S1C–S1F). The known molecular functions of the host factors weredetermined with the use of bioinformatics and multiple datasets (gray ovals). Host factors identified in the human siRNA screen (blue), the human orthologs of proteins identified in the fly-based screen (pink), factors that were found in both human and fly screens (green), and bridging proteins that were not detected but none-the-less generate potentially insightful interactions (gray) are shown. Double borders signify that the candidate is present in the Reactome influenza A virus infection pathway (Vastrik et al., 2007). Solid lines between genes indicate a protein interaction in human or other species. Dotted lines indicate inferred interaction from literature or annotation. Viral RNA (vRNA), viral complementary RNA (cRNA).




Figure 7. IFITM Proteins Act as Antiviral Restriction Factors
A schematic model of the influenza A virus life cycle, the induction of IFITM proteins, and their role in blocking Influenza A virus infection. IFITM1, 2, and 3 are represented by the three multitransmembrane
proteins. Red lettering indicates possible mechanisms of restriction: IFITM proteins may (A) sequester the incoming viruses at or near the surface, (B) block viral receptors from interacting with host receptors (shown in orange), (C) prevent endocytosis or viral membrane fusion, (D) act as receptors and, after binding the virus, signal to effectors.