丙型肝炎病毒诱导和逃逸宿主细胞干扰素信号通路的机制研究

项目名称： 丙型肝炎病毒诱导和逃逸宿主细胞干扰素信号通路的机制研究

项目编号： No.81330039

项目类型： 重点项目

立项/批准年度： 2014

项目学科： 医药、卫生

项目作者： 钟劲

作者单位： 中国科学院上海巴斯德研究所

项目金额： 290万元

中文摘要： 丙肝病毒（HCV）能形成慢性感染，其自发清除与编码Ⅲ型干扰素的IL28B基因附近的SNP相关，提示Ⅲ型干扰素通路在HCV的慢性感染中有着重要作用。之前的研究结果表明，含有HCV基因组末端的RNA（3’UTR）转染到肝细胞后，可以被宿主RIG-I识别，进而通过VISA诱导I型和Ⅲ型干扰素的产生。但是由于病毒编码的NS3蛋白酶能切割VISA来抑制这一通路，感染HCV的肝细胞并不能表达I型和Ⅲ型干扰素。最近我们通过阻断NS3对VISA的切割首次建立了HCV感染激活肝细胞干扰素信号通路的体系，意外地发现HCV在自然感染情况下诱导的干扰素产生并不依赖于病毒的3'UTR和宿主RIG-I;此外HCV的NS4B可通过和宿主STING的结合来阻碍干扰素的激活。本课题在这些重要前期工作基础上深入研究HCV感染诱导宿主干扰素信号通路的分子机制，探索HCV逃逸干扰素反应的新机制及其在病毒慢性感染中的作用。

中文关键词： 丙型肝炎病毒;固有免疫;干扰素;病原相关分子模式;模式识别受体

英文摘要： Hepatitis C virus (HCV) infection can be persistent, and its spontaneous clearance is associated with the single-nucleotide polymorphisms (SNP) located near IL28B encoding a type III interferon, suggesting that type III interferon may play an important role in the progression and outcome of the HCV induced diseases. Many previous studies including ours show that HCV’s RNA genome contains a Pathogen-Associated Molecular Pattern (PAMP) in its 3’ untranslated region (3’UTR), which, after being delivered into hepatocytes by transfection, can be recognized by host Pattern Recognition Receptor (PRR) RIG-I to activate type I and type III interferon production via VISA, an important adaptor protein in the interferon signaling pathway. However, because the virus-encoded NS3/4A protease could suppress this signaling pathway by cleaving VISA, HCV infection does not trigger the type I and type III interferon production in hepatocytes. Recently, we develop a hepatic cell line in which VISA is no longer cleaved by the NS3/4A protease such that can produce interferon upon HCV infection. Remarkably and unexpectedly, we found that HCV infection-induced interferon production is not dependent upon the 3’UTR of viral genome and host RIG-I, the previously reported PAMP and PRR, respectively. In addition, we found that HCV encoded NS4B protein can reduce the interferon signaling by interacting with the host protein STING, another recently discovered adaptor protein to promote the interferon production in response to double-stranded DNA transfection, bacterial and RNA virus infection. Based on these novel preliminary results, we will investigate how HCV infection activates the interferon signaling pathway, and how HCV possibly evades the host’s anti-virus interferon response, and explore the roles and significance of these new mechanisms in chronicity of HCV infection.

英文关键词： hepatitis C virus;innate immunity;Interferon;PAMP;pathogen-recognition receptors