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：
7772297
负责人：
KUI LI
金额：
$ 25.15万
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/7772297
关键词：
Antiviral Agents Antiviral Response Cells Chronic Chronic Hepatitis Cirrhosis Complex 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 Primary carcinoma of the liver cells RNA Viruses RNA replication Recruitment Activity Research Role Signal Pathway Signal Transduction Supporting Cell Tretinoin Viral Virus Diseases Virus Replication anti-hepatitis C cytokine design human IRF3 protein human TLR3 protein interferon regulatory factor-3 neoplastic novel therapeutic intervention pathogen permissiveness reconstitution response sensor transcription factor viral RNA virus host interaction

项目摘要

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)，一种经常造成持续感染的正链 RNA 病毒导致慢性肝炎、肝硬化和肝癌。然而，人们对肝细胞如何感知的知之甚少。 HCV 感染并启动保护反应。我们最近证明非肿瘤性 PH5CH8 肝细胞含有两种不同的抗病毒信号通路：Toll 样受体 3 (TLR3) 和视黄酸 - 诱导基因 I (RIG-I)，识别病毒双链 (ds) RNA 并产生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中的作用控制HCV感染。虽然 RIG-I 信号最近被证明有助于感知和限制细胞内 HCV RNA 复制、TLR3 信号传导在细胞识别和控制 HCV 中的作用感染仍然未知，因为之前的研究都是在肝癌 Huh7 细胞中进行的，这些细胞缺乏功能性 TLR3 通路。我们假设 TLR3 信号传导是重要的抗病毒机制肝细胞，并有助于宿主自身和/或与其他抗病毒药物协同防御 HCV 信号机制。我们提出以下目标： 1. 确定 TLR3 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TLR3信号通路在肝细胞中。 3. 表征肝细胞中 TLR3 信号传导的机制。这项拟议的研究将增进我们对丙型肝炎发病机制中病毒与宿主相互作用以及丙型肝炎的作用的了解先天免疫控制丙型肝炎病毒感染，这将有利于新治疗干预措施的设计用于丙型肝炎病毒感染。