【摘 要】
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Hepatitis C virus(HCV)is an important cause of human liver diseases.Humans and chimpanzees are the only known species susceptible to HCV infection.The restr
【机 构】
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KeyLaboratoryofAnimalModelsandHumanDiseaseMechanismsoftheChineseAcademyofSciences&YunnanProvince,Kun
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Hepatitis C virus(HCV)is an important cause of human liver diseases.Humans and chimpanzees are the only known species susceptible to HCV infection.The restricted species tropism of HCV is the major limitation to HCV research and development of drugs and vaccines.The tree shrew(Tupaia belangeri),a close relative of primates,is emerging as a potential animal model for investigating the HCV infection.Human MAVS(hMAVS,also known as IPS-1,VISA,or Cardif)is essential for the antiviral innate immunity,which is inactivated by the HCVNS3/4Aprotease.In this study,we identified and characterized the functions of the tree shrew MAVS gene(tMAVS)in the context of HCV infection.Conservatively,RNA and DNA viruses induced the expression of tMAVS.Ectopic-expression of tMAVS markedly potentiated the virus-triggered activation of IRF3,NF-κB and interferon-β(IFN-β),whereas knockdown of tMAVS displayed the opposite effect.Notably,HCV was co-localized with tMAVS in the tree shrew liver-derived cells,and cleaved tMAVS at itsCys-508 via the corresponding NS3/4A protease.Interestingly,site Glu-506 in tMAVS,although not conserved relative to Val-506 inhMAVS,could support the cleavage role of NS3/4A.Unexpectedly,HCV NS3/4Acould only impair the IRF3-mediated induction of IFN-β,but not the activation of the NF-κB signaling in the tree shrew cells,which might account for the low infection rate and HCV titers in the tree shrew model.Collectively,this study revealed the conservation and diversification of the MAVS antiviral signaling pathways,demonstrating the practicality of the tree shrew for studying HCV infection.
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