Differential, type i interferon-mediated autophagic trafficking of hepatitis C virus proteins in mouse liver

Mayura M. Desai, Bin Gong, Tehsheng Chan, Robert A. Davey, Lynn Soong, Andrey A. Kolokoltsov, Jiaren Sun

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

Background & Aims: The hepatitis C virus (HCV) serine protease NS3/4A can cleave mitochondria-associated antiviral signaling protein (MAVS) and block retinoic acidinducible gene Imediated interferon (IFN) responses. Although this mechanism is thought to have an important role in HCV-mediated innate immunosuppression, its significance in viral persistence is not clear. Methods: We generated transgenic mice that express the HCV NS3/4A proteins specifically in the liver and challenged the animals with a recombinant vesicular stomatitis virus, a synthetic HCV genome, IFN alfa, or IFN beta. We evaluated the effects of HCV serine protease on the innate immune responses and their interactions. Results: Expression of HCV NS3/4A resulted in cleavage of intrahepatic MAVS; challenge of transgenic mice with vesicular stomatitis virus or a synthetic HCV genome induced strong, type I IFN-mediated responses that were not significantly lower than those of control mice. Different challenge agents induced production of different ratios of IFN alfa and beta, resulting in different autophagic responses and vesicular trafficking patterns of endoplasmic reticulum- and mitochondria-associated viral proteins. IFN beta promoted degradation of the viral proteins by the autolysosome. Variant isoforms of MAVS were associated with distinct, type I IFN-mediated autophagic responses; these responses have a role in trafficking of viral components to endosomal compartments that contain Toll-like receptor3. Conclusions: IFN beta mediates a distinct autophagic mechanism of antiviral host defense. MAVS has an important role in type I IFN-induced autophagic trafficking of viral proteins.

Original languageEnglish (US)
Pages (from-to)674-685.e6
JournalGastroenterology
Volume141
Issue number2
DOIs
StatePublished - Aug 2011

Keywords

  • Autophagy
  • Liver Disease
  • RIG-I
  • TLR3

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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