Role of TLR3 Signaling in Control of HCV

TLR3 信号传导在 HCV 控制中的作用

• 批准号: 7367012
• 负责人: KUI LI
• 金额: $ 12.69万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-15 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7367012
• 关键词: Antiviral Agents; Antiviral Response; Cells; Chronic; Chronic Hepatitis; Cirrhosis; Complex; Disruption; Double-Stranded RNA; Genes; Goals; Hepatitis C; Hepatitis C virus; Hepatocyte; Host Defense; Human Virus; Infection; Interferon Activation; Interferons; Investigation; Knowledge; Lead; Life; Liver diseases; Malignant neoplasm of liver; Mammalian Cell; Mediating; NF-kappa B; Natural Immunity; Outcome; Pathogenesis; Pathway interactions; Personal Satisfaction; Primary carcinoma of the liver cells; RNA Viruses; RNA replication; Recruitment Activity; Research; Role; Signal Pathway; Signal Transduction; Supporting Cell; Therapeutic Intervention; Tretinoin; Viral; Virus Diseases; Virus Replication; anti-hepatitis C; cytokine; design; human IRF3 protein; human TLR3 protein; interferon regulatory factor-3; neoplastic; novel therapeutics; pathogen; permissiveness; reconstitution; response; sensor; transcription factor; viral RNA; virus host interaction

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 sensing and limiting intracellular HCV RNA replication, the role of TLR3 signaling in cellular recognition and control of HCV infection remains unknown, 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 by itself and/or in synergy with other antiviral signaling mechanisms. We propose the following aims: 1. Determine whether TLR3 signaling contributes to cellular control of HCV replication. 2. Determine whether HCV replication activates TLR3 signaling pathway in hepatocytes. 3. Characterize the mechanisms of TLR3 signaling in hepatocytes. 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 benefit the design of new therapeutic interventions for HCV infection.

先天性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），一种经常引起持续感染的正链RNA病毒 导致慢性肝炎、肝硬化和肝癌。然而，关于肝细胞如何感知 HCV感染并启动保护性反应。我们最近发现，非肿瘤性PH 5CH 8 肝细胞含有两种不同的抗病毒信号通路，Toll样受体3（TLR 3）和视黄酸， 诱导基因I（RIG-I），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肝细胞凋亡中的作用。 控制HCV感染。虽然RIG-I信号传导最近被证明有助于感知和限制 细胞内HCV RNA复制，TLR 3信号在细胞识别和控制HCV中的作用 感染仍然是未知的，因为以前的研究都是在肝肿瘤Huh 7细胞中进行的， 功能性TLR 3通路。我们假设TLR 3信号传导是一种重要的抗病毒机制， 肝细胞，并有助于宿主防御HCV本身和/或协同其他抗病毒药物 信号机制。我们提出以下目标：1.确定TLR 3信号传导是否有助于 HCV复制的细胞控制。2.确定HCV复制是否激活TLR 3信号通路 在肝细胞中。3.描述肝细胞中TLR 3信号传导的机制。这项拟议的研究 将促进我们对丙型肝炎发病机制中病毒-宿主相互作用以及 先天免疫在控制HCV感染中的作用，这将有利于设计新的治疗干预措施 HCV感染。