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

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.

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。

丙肝病毒（HCV）感染人肝细胞，引发慢性肝炎，并进一步发展为肝纤维化、肝硬化和肝癌。宿主的固有免疫应答，尤其是干扰素信号通路的激活，是宿主抵抗病毒感染的重要机制之一。同时，HCV能够有效逃逸宿主的固有免疫应答，是其建立持续性感染的关键原因之一。本课题聚焦HCV和肝细胞固有免疫系统的相互作用，开展了如下研究：肝细胞RIG-I样模式识别受体分子（RLR）识别HCV感染的分子机制；宿主固有免疫应答抑制HCV感染的新机制；HCV逃逸肝细胞TLR3介导的干扰素信号通路的机制。. 本项目顺利完成了各项预期目标，发表通讯作者文章9篇，培养博士后1名，博士研究生7名，在结题验收答辩中获得A评分。重要研究成果总结如下：1、发现了MDA5和LGP2是识别HCV的关键模式识别受体，明确了不同RLR家族成员在HCV感染诱导的干扰素信号通路中的作用，并提出了病毒感染和病毒核酸转染在激活固有免疫应答中存在差异的新观点。这部分工作分别发表在Journal of Hepatology和Hepatology上，均获得Faculty of 1000的推荐。2、揭示了抗病毒固有免疫效应分子25-羟胆固醇合成酶（CH25H）通过调控宿主脂代谢抑制HCV复制的分子机制，阐述了病毒诱导CH25H表达的调控机制，这部分结果发表在Journal of Virology上。3、阐明了HCV逃逸TLR3介导的干扰素信号通路的新机制，发现HCV编码的病毒蛋白NS4B可以通过激活宿主细胞中的Caspase8，从而促进TLR3关键接头蛋白TRIF的降解，最终抑制干扰素信号通路。该研究提出了HCV逃逸宿主固有免疫应答的新机制，发表在PLoS Pathogens上。通过本课题的研究，我们揭示了HCV激活及逃逸干扰素信号通路的新机制，增加了对抗病毒固有免疫应答的新认识。

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