Role of TLR3 Signaling in Control of HCV

固有的细胞抗病毒防御能力可能会影响许多人类病毒感染的结果， 包括丙型肝炎病毒(丙型肝炎病毒)，一种经常导致持续性感染的正链RNA病毒 导致慢性肝炎、肝硬变和肝癌。然而，人们对肝细胞如何感知知之甚少。 丙型肝炎病毒感染并启动保护性反应。我们最近表明，非肿瘤性PH5CH8 肝细胞含有两条不同的抗病毒信号通路，Toll样受体3(TLR3)和维甲酸- 可诱导基因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中的作用 控制丙型肝炎病毒感染。而RIG-I信号最近被证明有助于感知和限制 细胞内丙型肝炎病毒RNA复制，TLR3信号在细胞识别和控制丙型肝炎病毒中的作用 感染情况尚不清楚，因为之前的研究都是在缺乏 一个有功能的TLR3途径。我们推测TLR3信号转导通路是抗病毒的一个重要机制。 肝细胞，单独和/或与其他抗病毒药物协同作用有助于宿主防御丙型肝炎病毒 信令机制。我们提出了以下目标：1.确定TLR3信号是否参与 丙型肝炎病毒复制的细胞控制。2.确定丙型肝炎病毒复制是否激活TLR3信号通路 在肝细胞中。3.研究TLR3信号在肝细胞中的作用机制。这项拟议的研究 将促进我们对病毒-宿主相互作用在丙型肝炎发病机制中的作用以及 先天免疫在控制丙型肝炎病毒感染中的作用，这将有助于设计新的治疗干预措施 用于丙型肝炎病毒感染。

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.