Role of TLR3 Signaling in Control of HCV

TLR3 信号传导在 HCV 控制中的作用

基本信息

批准号：
7680814
负责人：
KUI LI
金额：
$ 12.88万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-03-15 至 2012-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7680814
关键词：
Antiviral Agents Antiviral Response Cell surface Cells Chronic Chronic Hepatitis Cirrhosis Complex Confocal Microscopy Disruption Double-Stranded RNA Ectopic Expression Endosomes Flow Cytometry Genes Goals Hepatitis C Hepatitis C virus Hepatocyte Host Defense Human Virus Infection Interferons Investigation Knowledge Lead Life Liver diseases Malignant neoplasm of liver Mammalian Cell Mediating Mediator of activation protein Mitochondria NF-kappa B Natural Immunity Outcome Pathogenesis Pathway interactions Patients Primary carcinoma of the liver cells RNA Viruses RNA replication Reporting Research Role Signal Pathway Signal Transduction Signaling Protein Structure Supporting Cell TNF receptor-associated factor 3 Therapeutic Intervention Tretinoin Viral Virus Diseases Virus Replication anti-hepatitis C cell type cytokine design human IRF3 protein human TLR3 protein improved interferon regulatory factor-3 liver biopsy neoplastic novel therapeutics pathogen permissiveness reconstitution response sensor transcription factor viral RNA virus host interaction

项目摘要

DESCRIPTION: Innate cellular antiviral defenses are likely to influence the outcome of infections by many human viruses, including hepatitis C virus (HCV), a positive strand RNA virus that frequently establishes persistent infections leading to chronic hepatitis, cirrhosis and liver cancer. However, little is known about how hepatocytes sense HCV infection and initiate protective responses. We have recently shown that non-neoplastic PH5CH8 hepatocytes contain two distinct antiviral signaling pathways, Toll-like receptor 3 (TLR3) and retinoic acid-inducible gene I (RIG-I), to recognize viral double-stranded (ds) RNA and lead to subsequent interferon antiviral response. Our long-term goal is to elucidate the role of these signaling pathways in hepatocellular control of HCV infection. While RIG-I signaling was recently shown to contribute to sense intracellular HCV RNA replication, the role of TLR3 signaling in recognition and control of HCV infection remains to be determined, as previous investigations were all conducted in hepatoma Huh7 cells which lack a functional TLR3 pathway. We hypothesize that TLR3 signaling is an important antiviral mechanism of hepatocytes, and contributes to host defenses against HCV. We propose three aims for this application: (1) Determine the subcellular localization of TLR3 and the mechanism of TLR3 signaling in hepatocytes where it is initiated and to what extent it cross-talks with the RIG-I pathway. (2) Determine whether structured HCV RNA and HCV infection activate TLR3 signaling pathway in TLR3 reconstituted Huh cells and whether TLR3 is associated with HCV replication complex in cells supporting HCV replication. (3) Determine whether TLR3 signaling contributes to hepatocellular control of HCV replication. This proposed research shall advance our knowledge regarding virus-host interactions in hepatitis C pathogenesis and the role of innate immunity in controlling HCV infection, which would potentially benefit the design of new therapeutic interventions for HCV infection.

描述：先天细胞抗病毒防御可能会影响许多人类病毒感染的结果，包括丙型肝炎病毒（HCV），这是一种经常建立持续感染的阳性链RNA病毒，导致慢性肝炎，cirrhosis和肝癌。但是，关于肝细胞如何感知HCV感染并启动保护性反应知之甚少。我们最近表明，非肿瘤性PH5CH8肝细胞包含两个不同的抗病毒信号通路，Toll样受体3（TLR3）和视黄酸诱导的基因I（RIG-I），以识别病毒双链（DS）RNA并导致随后的干扰素抗病毒反应。我们的长期目标是阐明这些信号通路在HCV感染的肝细胞控制中的作用。尽管最近显示RIG-1信号传导有助于感官细胞内HCV RNA复制，但TLR3信号传导在识别和控制HCV感染中的作用仍有待确定，因为先前的研究都在缺乏功能性TLR3途径的Hepatoma HuH7细胞中进行。我们假设TLR3信号传导是肝细胞的重要抗病毒机制，并有助于针对HCV的宿主防御。我们提出了针对此应用的三个目的：（1）确定TLR3的亚细胞定位以及肝细胞中TLR3信号传导的机理，并在多大程度上与RIG-I途径交叉呼声。（2）确定结构化HCV RNA和HCV感染是否激活TLR3重构的HuH细胞中的TLR3信号通路，以及TLR3是否与支持HCV复制的细胞中的HCV复制复合物相关。（3）确定TLR3信号是否有助于HCV复制的肝细胞控制。这项拟议的研究应提高我们对丙型肝炎发病机理中病毒宿主相互作用的知识以及先天免疫在控制HCV感染中的作用，这可能会受益于针对HCV感染的新治疗干预措施的设计。