title: Control of hepatitis C virus replication in mouse liver-derived cells by MAVS-dependent production of type I and type III interferons.
abstract: Hepatitis C virus (HCV) efficiently infects only humans and chimpanzees. Although the detailed mechanisms responsible for this narrow species tropism remain elusive, recent evidence has shown that murine innate immune responses efficiently suppress HCV replication. Therefore, poor adaptation of HCV to evade and/or counteract innate immune responses may prevent HCV replication in mice. The HCV NS3-4A protease cleaves human MAVS, a key cellular adaptor protein required for RIG-I-like receptor (RLR)-dependent innate immune signaling. However, it is unclear if HCV interferes with mouse MAVS function equally well. Moreover, MAVS-dependent signaling events that restrict HCV replication in mouse cells were incompletely defined. Thus, we quantified the ability of HCV NS3-4A to counteract mouse and human MAVS. HCV NS3-4A similarly diminished both human and mouse MAVS-dependent signaling in human and mouse cells. Moreover, replicon-encoded protease cleaved a similar fraction of both MAVS variants. Finally, FLAG-tagged MAVS proteins repressed HCV replication to similar degrees. Depending on MAVS expression, HCV replication in mouse liver cells triggered not only type I but also type III IFNs, which cooperatively repressed HCV replication. Mouse liver cells lacking both type I and III IFN receptors were refractory to MAVS-dependent antiviral effects, indicating that the HCV-induced MAVS-dependent antiviral state depends on both type I and III IFN receptor signaling.
  
  
  OBJECTIVE
  In this study, we found that HCV NS3-4A similarly diminished both human and mouse MAVS-dependent signaling in human and mouse cells. Therefore, it is unlikely that ineffective cleavage of mouse MAVS per se precludes HCV propagation in immunocompetent mouse liver cells. Hence, approaches to reinforce HCV replication in mouse liver cells (e.g., by expression of essential human replication cofactors) should not be thwarted by the poor ability of HCV to counteract MAVS-dependent antiviral signaling. In addition, we show that mouse MAVS induces both type I and type III IFNs, which together control HCV replication. Characterization of type I or type III-dependent interferon-stimulated genes in these cells should help to identify key murine restriction factors that preclude HCV propagation in immunocompetent mouse liver cells.
authors.affiliation: Institute of Experimental Virology, Twincore Centre for Experimental and Clinical Infection Research, Hanover, Germany.
authors.lastname: Anggakusuma
authors.affiliation: Institute of Experimental Virology, Twincore Centre for Experimental and Clinical Infection Research, Hanover, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Frentzen
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hanover, Germany.
authors.forename: Engin
authors.initials: E
authors.lastname: Gürlevik
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hanover, Germany Translational Research Group, Twincore Centre for Experimental and Clinical Infection Research, Hanover, Germany.
authors.forename: Qinggong
authors.initials: Q
authors.lastname: Yuan
authors.affiliation: Institute of Experimental Virology, Twincore Centre for Experimental and Clinical Infection Research, Hanover, Germany.
authors.forename: Eike
authors.initials: E
authors.lastname: Steinmann
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hanover, Germany Translational Research Group, Twincore Centre for Experimental and Clinical Infection Research, Hanover, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Ott
authors.affiliation: Department of Virology, University of Freiburg, Freiburg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Staeheli
authors.affiliation: Institute for Clinical Chemistry and Clinical Pharmacology, University Hospital, University of Bonn, Bonn, Germany.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Schmid-Burgk
authors.affiliation: Institute for Clinical Chemistry and Clinical Pharmacology, University Hospital, University of Bonn, Bonn, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Schmidt
authors.affiliation: Institute for Clinical Chemistry and Clinical Pharmacology, University Hospital, University of Bonn, Bonn, Germany.
authors.forename: Veit
authors.initials: V
authors.lastname: Hornung
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hanover, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Kuehnel
authors.affiliation: Institute of Experimental Virology, Twincore Centre for Experimental and Clinical Infection Research, Hanover, Germany Thomas.pietschmann@twincore.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Pietschmann
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D016174:Hepacivirus / Q000276:immunology / Q000502:physiology*; D022781:Hepatocytes / Q000276:immunology* / Q000821:virology; D054884:Host-Pathogen Interactions; D006801:Humans; D007372:Interferons / Q000276:immunology* / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D017361:Viral Nonstructural Proteins / Q000378:metabolism*; D014779:Virus Replication; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D007372:Interferons; D017361:Viral Nonstructural Proteins; C512612:MAVS protein, mouse; C505371:MAVS protein, human; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C093542:NS4 protein, hepatitis C virus