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Distinct patterns of IFITM-mediated restriction of filoviruses, SARS coronavirus, and influenza A virus

I-Chueh Huang1, Charles C Bailey, Jessica L Weyer

  • 1Department of Microbiology and Molecular Genetics, Harvard Medical School, New England Primate Research Center, Southborough, Massachusetts, United States of America. I-Chueh_Huang@hms.harvard.edu

Plos Pathogens
|January 22, 2011
PubMed

Insights

Interferon-inducible transmembrane proteins (IFITMs) restrict a broad range of enveloped viruses, including influenza, filoviruses (Ebola, Marburg), and SARS-CoV. These proteins act late in the endocytic pathway to inhibit viral entry and replication.

Area of Science:

  • Virology
  • Cell Biology
  • Immunology

Background:

  • Interferon-inducible transmembrane proteins (IFITMs) are known to restrict influenza A virus (IAV) infection.
  • The specific mechanisms and broad spectrum of IFITM antiviral activity remain under investigation.

Purpose of the Study:

  • To investigate the role of IFITM proteins in restricting the entry and replication of filoviruses (Marburg virus, Ebola virus) and SARS coronavirus.
  • To elucidate the stage of the endocytic pathway where IFITM-mediated restriction occurs.

Main Methods:

  • Infection assays using pseudotyped and replication-competent viruses (IAV, MARV, EBOV, SARS-CoV).
  • Assessment of IFITM protein expression and localization.
  • Analysis of viral entry and replication kinetics.
  • Investigation of the role of endosomal acidification and cathepsin activity.

Main Results:

  • IFITM proteins restrict entry mediated by filovirus glycoproteins (GP(1,2)) and SARS-CoV spike (S) protein, in addition to IAV hemagglutinin (HA).
  • IFITM-mediated restriction of filoviruses and SARS-CoV differs from IAV, with IFITM1 showing stronger restriction of filoviruses and IFITM3 showing weaker restriction.
  • IFITM proteins act at a late stage of the endocytic pathway, independent of cellular cathepsin activity or access to acidic compartments.
  • Murine Ifitm5 and Ifitm6 specifically inhibit filovirus entry but not IAV.

Conclusions:

  • IFITM proteins exhibit broad-spectrum antiviral activity against enveloped viruses, including filoviruses and coronaviruses.
  • IFITM-mediated restriction is dependent on the specific viral glycoprotein and occurs late in endocytosis.
  • IFITMs differentially restrict viral tropism, suggesting a complex role in innate immunity.

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