Role of TLR3 Signaling in Control of HCV

描述（由申请方提供）：先天性细胞抗病毒防御可能影响许多人类病毒感染的结果，包括丙型肝炎病毒（HCV），一种常导致慢性肝炎、肝硬化和肝癌的持续感染的正链RNA病毒。然而，肝细胞如何感知HCV感染并启动保护性反应却知之甚少。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），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肝细胞控制HCV感染中的作用。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，但TLR 3信号传导在细胞识别和控制HCV感染中的作用仍然未知，因为以前的研究都是在缺乏功能性TLR 3途径的肝癌Huh 7细胞中进行的。我们假设TLR 3信号传导是肝细胞的重要抗病毒机制，并且有助于宿主自身和/或与其他抗病毒信号传导机制协同防御HCV。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复制是否激活肝细胞中的TLR 3信号通路。3.描述肝细胞中TLR 3信号传导的机制。这项研究将进一步提高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感染中的作用的认识，这将有利于设计新的HCV感染治疗干预措施。

DESCRIPTION (provided by applicant): 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.