Xiang Yu, Tang Jing-Jie, Tao Wanyin, Cao Xuezhi, Song Bao-Liang, Zhong Jin
Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
The State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
J Virol. 2015 Jul;89(13):6805-16. doi: 10.1128/JVI.00587-15. Epub 2015 Apr 22.
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 postentry stage. CH25H inhibits HCV infection by suppressing the maturation of SREBPs, critical transcription factors for host lipid biosynthesis. Interestingly, CH25H is upregulated upon poly(I · C) treatment or HCV infection in hepatocytes, which triggers type I and III interferon responses, suggesting that 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 humans 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.
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 postentry stage via suppressing the maturation of transcription factor SREBPs that regulate lipid biosynthesis. Furthermore, we found that CH25H expression is upregulated 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 showing 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.
丙型肝炎病毒（HCV）是黄病毒科的一种单链正义RNA病毒，可导致慢性肝病，包括肝炎、肝硬化和癌症。HCV感染严重依赖宿主脂质代谢，而脂质代谢参与病毒生命周期的各个阶段，包括病毒进入、复制、组装和释放。25-羟基胆固醇（25HC）在调节脂质代谢、调节免疫反应和抑制病毒病原体方面发挥着关键作用。在本研究中，我们表明25HC及其合成酶胆固醇25-羟化酶（CH25H）在病毒进入后阶段有效抑制HCV感染。CH25H通过抑制甾醇调节元件结合蛋白（SREBPs）的成熟来抑制HCV感染，SREBPs是宿主脂质生物合成的关键转录因子。有趣的是，在肝细胞中，多聚（I·C）处理或HCV感染后CH25H会上调，这会触发I型和III型干扰素反应，表明CH25H的诱导构成宿主固有免疫反应的一部分。令我们惊讶的是，与在小鼠中的研究不同，在人类细胞中干扰素不会诱导CH25H，并且敲低信号转导和转录激活因子1（STAT-1）对CH25H的诱导没有影响，这表明CH25H在人类中不是干扰素刺激基因，而是代表宿主对病毒感染的一种主要和直接反应。最后，在人类肝细胞中敲低CH25H会显著增加HCV感染。总之，我们的结果表明，CH25H通过调节宿主脂质代谢构成针对HCV感染的主要固有反应。操纵CH25H的表达和功能应为抗HCV治疗提供一种新策略。
最近的研究扩展了氧化甾醇在调节免疫反应和对抗病毒病原体方面的关键作用。在这里，我们表明氧化甾醇之一25HC及其合成酶CH25H通过抑制调节脂质生物合成的转录因子SREBPs的成熟，在病毒进入后阶段有效抑制HCV感染。此外，我们发现多聚（I·C）刺激或HCV感染后CH25H表达上调，表明CH25H的诱导构成宿主固有免疫反应的一部分。有趣的是，与在小鼠中的研究表明CH25H是干扰素刺激基因不同，在人类细胞中干扰素不能诱导CH25H，而是代表宿主对病毒感染的一种主要和直接反应。我们的研究表明，CH25H的诱导代表了宿主针对病毒感染的一种重要固有反应，并突出了脂质效应物在宿主抗病毒策略中的作用。
