TXNIP促进HCV复制与逃避宿主固有免疫的机制

Hepatitis C virus replicates in hepatocytes without causing cytopathic effect, and efficiently escape from the cellular innate immunity, which constitute the major reason for the high incidence of chronic infection of this virus. We found that HCV infection powerfully increased expression of thioredoxin interacting protein (TXNIP) in human hepatocellular carcinoma Huh7 cell line by transcriptome sequencing. In the liver tissue of human CD81 and occludin transgene（huC/OTg）mice infected with HCVcc, TXNIP expression was also greatly elevated. Further analysis showed that knocking-down TXNIP expression by RNA interference greatly reduced HCV replication, and that typeⅠand type Ⅲ interferons induced TXNIP expression. Since TXNIP is an important regulator molecule involving in several biological processes, it is deserved to define the specific function of TXNIP that contribute HCV infection. In this study, Huh7 cells and huC/OTg mice will be used as models for this purpose. From the perspectives of oxidative stress and endoplasmic reticulum stress induced by HCV infection, the mechanisms of TXNIP regulates autophagy, mitophagy and unfolded protein response to enhance HCV replication, protect hepatocytes against apoptosis due to excessive stress responses, inhibit interferons expression and their anti-viral activity will be explored. Hopefully, new strategies that HCV using host factors to achieve its persistent infection would be discovered.

HCV以非致细胞病变方式在肝细胞内复制，并逃避细胞固有免疫，这是HCV高发慢性感染的重要原因，认识其机制对于研发抗HCV新药具有重要意义。我们对HCV感染的Huh7细胞进行的转录组测序显示，HCV感染显著上调硫氧还蛋白互作蛋白（TXNIP）的表达；在HCVcc感染的人CD81和occludin转基因（huC/OTg）小鼠，肝组织内TXNIP也显著上调；抑制TXNIP的表达显著降低HCV的复制；I和III型干扰素均能诱导TXNIP的表达。鉴于TXNIP在细胞多种生物途径中的重要调控作用，本课题将以Huh7细胞以及huC/OTg小鼠为模型，以HCV感染诱导的肝细胞氧化应激和内质网应激为切入点，深入探讨TXNIP通过调控细胞自噬、线粒体自噬、非折叠蛋白应答促进HCV复制，保护细胞免于过度应激反应引起的凋亡，以及抑制干扰素的表达与抗病毒活性的可能途径，揭示HCV利用宿主因子实现其持续感染的新机制。

HCV以非致细胞病变方式在肝细胞内复制，并逃避细胞固有免疫，这是HCV高发慢性感染的重要原因，认识其机制对于研发抗HCV新药具有重要意义。本课题对HCV感染的Huh7细胞进行的转录组测序显示，HCV感染显著上调硫氧还蛋白互作蛋白（TXNIP）的表达；抑制TXNIP的表达显著降低HCV的复制；I和III型干扰素均能诱导TXNIP的表达。对HCV感染者以及健康人肝组织进行定量PCR检测，结果也显示与健康对照组相比，HCV感染者肝组织的TXNIP表达水平显著升高，HCV感染的小鼠模型也呈现类似表型，在感染后第10天以及8周检测，均显示肝组织内TXNIP表达水平显著升高。本研究还证实钙离子拮抗剂维拉帕米通过下调TXNIP的表达而抑制HCV感染。基于Huh7细胞水平的检测发现，HCV感染可显著上调多种细胞因子的表达，其中IL-11的表达上调通过STAT3信号通路上调TXNIP的表达。HCV感染小鼠模型外周血中IL-11水平也显著升高，且大剂量IL-11抗体能抑制小鼠血清中HCV病毒载量。本课题揭示了HCV慢性感染的新机制，并为认识其他黄病毒或嗜肝病毒的感染和致病机制以及防治药物研发提供了新线索。