巴斯德所发现宿主固有免疫反应抵御丙肝病毒感染新机制

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    丙型肝炎病毒(HCV)是人类的重要病原体，是导致慢性肝炎、肝硬化及肝癌的病原体之一。近年来尽管抗HCV药物研究取得重要进展，但高昂的价格将限制其广泛运用，而且目前缺乏针对HCV的有效疫苗。因此HCV对人类健康仍然造成很大的威胁。

　　中科院上海巴斯德研究所病毒性肝炎研究组博士研究生向禹在钟劲研究员的指导下，发现25羟基胆固醇及其合成酶25羟基胆固醇合成酶（CH25H）能够有效抑制HCV的感染。机制研究显示，CH25H通过影响甾醇调节元件结合蛋白（SREBP）的转录活性阻碍宿主脂类代谢合成，从而抑制病毒感染。进一步的研究工作发现，CH25H的表达是宿主应对病原体入侵产生的固有免疫反应。不同于之前小鼠实验的报道， CH25H不能直接被干扰素诱导，其诱导表达不依赖于JAK-STAT信号通路，而是一种直接的固有免疫反应，具有和干扰素转录激活类似的调控机制。这项研究发现了CH25H作为固有免疫反应抗HCV感染的重要作用，并阐述了其表达调控机制，为开发新的抗HCV治疗方法提供了重要参考。

　　该项工作的研究论文“Identification of cholesterol-25-hydroxylase as a novel host restriction factor as a part of primary innate immune responses against hepatitis C virus infection”于2015年4月22日由国际学术期刊Journal of Virology在线发表。

　　该项研究工作和武汉大学宋保亮教授研究组合作完成，得到了国家自然科学基金委、科技部973项目和国家传染病重大专项等项目的经费支持。

J Virol. 2015 Apr 22. pii: JVI.00587-15. [Epub ahead of print]
Identification of cholesterol-25-hydroxylase as a novel host restriction factor as a part of primary innate immune responses against hepatitis C virus infection.Xiang Y1, Tang JJ2, Tao W1, Cao X1, Song BL3, Zhong J4.
Author information

Abstract

Hepatitis C virus (HCV), a single-stranded positive-sense RNA virus of the Flaviviridae family, causes chronic liver diseases including hepatitis, cirrhosis and cancer. HCV infection is critically dependent on host lipid metabolism which contributes to all stages of the viral life cycle, including virus entry, replication, assembly and release. 25-hydroxycholesterol (25HC) plays a critical role in regulating lipid metabolism, modulating immune responses and suppressing viral pathogens. In this study, we showed that 25HC and its synthesizing enzyme cholesterol 25-hydroxylase (CH25H) efficiently inhibit HCV infection at a post-entry stage. CH25H inhibits HCV infection by suppressing the maturation of SREBPs, critical transcription factors for host lipid biosynthesis. Interestingly, CH25H is up-regulated upon poly(I:C) treatment or HCV infection in hepatocytes which triggers type I and III interferon responses, suggesting the CH25H induction constitutes a part of host innate immune response. To our surprise, in contrast to studies in mice, CH25H is not induced by interferons in human cells and knockdown of STAT-1 has no effect on the induction of CH25H, suggesting CH25H is not an interferon-stimulated gene in human, but rather represents a primary and direct host response to viral infection. Finally, knockdown of CH25H in human hepatocytes significantly increases HCV infection. In summary, our results demonstrate that CH25H constitutes a primary innate response against HCV infection through regulating host lipid metabolism. Manipulation of CH25H expression and function should provide a new strategy for anti-HCV therapeutics.

IMPORTANCE:

Recent studies have expanded the critical roles of oxysterols in regulating immune response and antagonizing viral pathogens. Here we showed that one of the oxysterols, 25HC and its synthesizing enzyme CH25H efficiently inhibit HCV infection at a post-entry stage via suppressing the maturation of transcription factor SREBPs that regulate lipid biosynthesis. Furthermore, we found that CH25H expression is up-regulated upon poly(I:C) stimulation or HCV infection, suggesting CH25H induction constitutes a part of host innate immune response. Interestingly, in contrast to studies in mice that ch25h is an interferon-stimulated gene, CH25H cannot be induced by interferons in human cells, but rather represents a primary and direct host response to viral infection. Our studies demonstrate that the induction of CH25H represents an important host innate response against virus infection and highlight the role of lipid effectors in host antiviral strategy.

钟劲研究员：

姓    名：	钟劲	学科类别：	病毒学
学    位：	博士	职    称：	研究员
电    话：	021-54923143	传    真：	021-54923142
职    务：	所长助理
电子邮件：	jzhong@sibs.ac.cn
通讯地址：	上海市徐汇区岳阳路320号生命科学大楼上海巴斯德研究所
教育背景：	1997-2003: 美国德克萨斯州大学奥斯汀分校微生物学博士； 1994-1997: 北京大学生物化学与分子生物学硕士； 1990-1994: 四川大学生物化学学士;
工作经历：	2006－至今　中国科学院上海巴斯德研究所病毒性肝炎研究组研究组长， 研究员 2003－2007　美国Scripps研究所分子及实验医学部博士后，研究助理
研究方向：	病毒性肝炎
获奖及荣誉：
承担科研项目：	艾滋病和病毒性肝炎等重大传染病防治科技重大专项“十一五” 艾滋病和病毒性肝炎等重大传染病防治科技重大专项“十二五” 国家重点基础研究发展计划（973计划） 国家自然科学基金 中国科学院知识创新工程重大项目 上海巴斯德健康研究基金 百人计划择优支持项目