title: Targeted induction of interferon-λ in humanized chimeric mouse liver abrogates hepatotropic virus infection.
abstract: OBJECTIVE
  The interferon (IFN) system plays a critical role in innate antiviral response. We presume that targeted induction of IFN in human liver shows robust antiviral effects on hepatitis C virus (HCV) and hepatitis B virus (HBV).
  
  
  METHODS
  This study used chimeric mice harboring humanized livers and infected with HCV or HBV. This mouse model permitted simultaneous analysis of immune responses by human and mouse hepatocytes in the same liver and exploration of the mechanism of antiviral effect against these viruses. Targeted expression of IFN was induced by treating the animals with a complex comprising a hepatotropic cationic liposome and a synthetic double-stranded RNA analog, pIC (LIC-pIC). Viral replication, IFN gene expression, IFN protein production, and IFN antiviral activity were analyzed (for type I, II and III IFNs) in the livers and sera of these humanized chimeric mice.
  
  
  RESULTS
  Following treatment with LIC-pIC, the humanized livers of chimeric mice exhibited increased expression (at the mRNA and protein level) of human IFN-λs, resulting in strong antiviral effect on HBV and HCV. Similar increases were not seen for human IFN-α or IFN-β in these animals. Strong induction of IFN-λs by LIC-pIC occurred only in human hepatocytes, and not in mouse hepatocytes nor in human cell lines derived from other (non-hepatic) tissues. LIC-pIC-induced IFN-λ production was mediated by the immune sensor adaptor molecules mitochondrial antiviral signaling protein (MAVS) and Toll/IL-1R domain-containing adaptor molecule-1 (TICAM-1), suggesting dual recognition of LIC-pIC by both sensor adaptor pathways.
  
  
  CONCLUSIONS
  These findings demonstrate that the expression and function of various IFNs differ depending on the animal species and tissues under investigation. Chimeric mice harboring humanized livers demonstrate that IFN-λs play an important role in the defense against human hepatic virus infection.
authors.affiliation: Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo, Japan.
authors.forename: Shin-ichiro
authors.initials: S
authors.lastname: Nakagawa
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hirata
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kameyama
authors.forename: Yuko
authors.initials: Y
authors.lastname: Tokunaga
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Nishito
authors.forename: Kazuko
authors.initials: K
authors.lastname: Hirabayashi
authors.forename: Junichi
authors.initials: J
authors.lastname: Yano
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ochiya
authors.forename: Chise
authors.initials: C
authors.lastname: Tateno
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Masashi
authors.initials: M
authors.lastname: Mizokami
authors.forename: Kyoko
authors.initials: K
authors.lastname: Tsukiyama-Kohara
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Inoue
authors.forename: Makoto
authors.initials: M
authors.lastname: Yoshiba
authors.forename: Akinori
authors.initials: A
authors.lastname: Takaoka
authors.forename: Michinori
authors.initials: M
authors.lastname: Kohara
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D002460:Cell Line; D002678:Chimera / Q000276:immunology*; D016174:Hepacivirus / Q000502:physiology*; D006515:Hepatitis B virus / Q000502:physiology*; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D007372:Interferons / Q000235:genetics*; D007378:Interleukins / Q000235:genetics; D008099:Liver / Q000166:cytology / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D051379:Mice; D020641:Polymorphism, Single Nucleotide; D012330:RNA, Double-Stranded / Q000235:genetics; D013045:Species Specificity; D015533:Transcriptional Activation; D000095022:Interferon Lambda
chemical_list: D007372:Interferons; D007378:Interleukins; D012330:RNA, Double-Stranded; C000624353:interferon-lambda, human; D000095022:Interferon Lambda
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