Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China.
Kunming Institute of Zoology - Chinese University of Hong Kong Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China.
J Immunol. 2020 Oct 15;205(8):2091-2099. doi: 10.4049/jimmunol.2000376. Epub 2020 Sep 9.
Hepatitis C virus (HCV) infection is the cause of severe liver disease in many people. The restricted species tropism of HCV hinders the research and development of drugs and vaccines. The Chinese tree shrew () is a close relative of primates and can be infected by HCV, but the underlying mechanisms are unknown. In this study, we have characterized the functions of tree shrew MAVS (tMAVS) in response to HCV infection and defined the capacity of HCV replication. HCV was shown to be colocalized with tMAVS in primary tree shrew hepatocytes and cleaved tMAVS at site Cys508 via its NS3/4A protease, with a modulating effect by site Glu of tMAVS. The tMAVS cleavage by HCV NS3/4A impaired the IRF3-mediated induction of IFN-β but maintained the activated NF-κB signaling in the tree shrew primary cells. Activation of the tMAVS-dependent NF-κB signaling inversely inhibited HCV replication and might limit the establishment of persistent infection. Overall, our study has revealed an elegant example of the balance between the host defenses and HCV infection via the MAVS-mediated antiviral signaling and has provided an insight into the mechanisms underpinning HCV infection in the Chinese tree shrew.
丙型肝炎病毒（HCV）感染是许多人严重肝脏疾病的病因。HCV 的受限物种嗜性阻碍了药物和疫苗的研发。中国树鼩（）是灵长类动物的近亲，可以感染 HCV，但潜在的机制尚不清楚。在本研究中，我们对树鼩 MAVS（tMAVS）在 HCV 感染反应中的功能进行了表征，并定义了 HCV 复制的能力。HCV 与原代树鼩肝细胞中的 tMAVS 共定位，并通过其 NS3/4A 蛋白酶在 Cys508 位点切割 tMAVS，tMAVS 的 Glu 位点具有调节作用。HCV NS3/4A 对 tMAVS 的切割削弱了 IRF3 介导的 IFN-β诱导，但维持了树鼩原代细胞中激活的 NF-κB 信号。tMAVS 依赖性 NF-κB 信号的激活反向抑制了 HCV 的复制，并可能限制持续感染的建立。总的来说，我们的研究揭示了通过 MAVS 介导的抗病毒信号在宿主防御和 HCV 感染之间的一种微妙平衡的范例，并深入了解了 HCV 在我国树鼩感染的机制。
