title: MAVS-dependent host species range and pathogenicity of human hepatitis A virus.
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.
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27517, USA. Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27517, USA.
authors.forename: Asuka
authors.initials: A
authors.lastname: Hirai-Yuki
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27517, USA. Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27517, USA.
authors.forename: Lucinda
authors.initials: L
authors.lastname: Hensley
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27517, USA. Department of Medicine, University of North Carolina, Chapel Hill, NC 27517, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: McGivern
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27517, USA. Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27517, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: González-López
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27517, USA. Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27517, USA.
authors.forename: Anshuman
authors.initials: A
authors.lastname: Das
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27517, USA. Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27517, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Feng
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27517, USA. Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27517, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Sun
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27517, USA. Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27517, USA. Department of Genetics, University of North Carolina, Chapel Hill, NC 27517, USA.
authors.forename: Justin E
authors.initials: JE
authors.lastname: Wilson
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27517, USA. Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27517, USA.
authors.forename: Fengyu
authors.initials: F
authors.lastname: Hu
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27517, USA. Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27517, USA.
authors.forename: Zongdi
authors.initials: Z
authors.lastname: Feng
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27517, USA.
authors.forename: William
authors.initials: W
authors.lastname: Lovell
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27517, USA. Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27517, USA. Department of Genetics, University of North Carolina, Chapel Hill, NC 27517, USA.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Misumi
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27517, USA. Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27517, USA. Department of Genetics, University of North Carolina, Chapel Hill, NC 27517, USA.
authors.forename: Jenny P-Y
authors.initials: JP
authors.lastname: Ting
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27517, USA. Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27517, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Montgomery
authors.affiliation: Department of Population Health and Pathobiology, North Carolina State University College of Veterinary Medicine, Raleigh, NC 27607, USA.
authors.forename: John
authors.initials: J
authors.lastname: Cullen
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27517, USA. Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27517, USA. Department of Genetics, University of North Carolina, Chapel Hill, NC 27517, USA.
authors.forename: Jason K
authors.initials: JK
authors.lastname: Whitmire
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27517, USA. Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27517, USA. Department of Medicine, University of North Carolina, Chapel Hill, NC 27517, USA. smlemon@med.unc.edu.
authors.forename: Stanley M
authors.initials: SM
authors.lastname: Lemon
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology*; D000818:Animals; D017209:Apoptosis; D004195:Disease Models, Animal; D006506:Hepatitis A / Q000276:immunology* / Q000473:pathology / Q000821:virology; D030041:Hepatitis A virus / Q000276:immunology*; D022781:Hepatocytes / Q000276:immunology / Q000473:pathology / Q000821:virology; D054884:Host-Pathogen Interactions / Q000276:immunology*; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000276:immunology; D050839:Interferon Regulatory Factor-7 / Q000235:genetics / Q000276:immunology; D007370:Interferon Type I / Q000276:immunology; D008099:Liver / Q000276:immunology* / Q000473:pathology / Q000821:virology; D051379:Mice; D018345:Mice, Knockout; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000276:immunology; D017471:Receptors, Interferon / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D013045:Species Specificity; D000096743:Interferon gamma Receptor
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I; D053633:Receptor, Interferon alpha-beta; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor; C512612:MAVS protein, mouse; C508032:Ifnar1 protein, mouse; C494233:Irf3 protein, mouse; C494235:Irf7 protein, mouse