MAVS-dependent host species range and pathogenicity of human hepatitis A virus

Science. 2016 Sep 30;353(6307):1541-1545. doi: 10.1126/science.aaf8325. Epub 2016 Sep 15.

Abstract

Hepatotropic viruses are important causes of human disease, but the intrahepatic immune response to hepatitis viruses is poorly understood because of a lack of tractable small- animal models. We describe a murine model of hepatitis A virus (HAV) infection that recapitulates critical features of type A hepatitis in humans. We demonstrate that the capacity of HAV to evade MAVS-mediated type I interferon responses defines its host species range. HAV-induced liver injury was associated with interferon-independent intrinsic hepatocellular apoptosis and hepatic inflammation that unexpectedly resulted from MAVS and IRF3/7 signaling. This murine model thus reveals a previously undefined link between innate immune responses to virus infection and acute liver injury, providing a new paradigm for viral pathogenesis in the liver.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / immunology*
  • Animals
  • Apoptosis
  • Disease Models, Animal*
  • Hepatitis A / immunology*
  • Hepatitis A / pathology
  • Hepatitis A / virology
  • Hepatitis A virus / immunology*
  • Hepatocytes / immunology
  • Hepatocytes / pathology
  • Hepatocytes / virology
  • Host-Pathogen Interactions / immunology*
  • Humans
  • Interferon Regulatory Factor-3 / genetics
  • Interferon Regulatory Factor-3 / immunology
  • Interferon Regulatory Factor-7 / genetics
  • Interferon Regulatory Factor-7 / immunology
  • Interferon Type I / immunology
  • Interferon gamma Receptor
  • Liver / immunology*
  • Liver / pathology
  • Liver / virology
  • Mice*
  • Mice, Knockout
  • Receptor, Interferon alpha-beta / genetics
  • Receptor, Interferon alpha-beta / immunology
  • Receptors, Interferon / genetics
  • Receptors, Interferon / immunology
  • Signal Transduction / immunology
  • Species Specificity

Substances

  • Adaptor Proteins, Signal Transducing
  • IPS-1 protein, mouse
  • Ifnar1 protein, mouse
  • Interferon Regulatory Factor-3
  • Interferon Regulatory Factor-7
  • Interferon Type I
  • Irf3 protein, mouse
  • Irf7 protein, mouse
  • Receptors, Interferon
  • Receptor, Interferon alpha-beta