Role of TLR3 Signaling in Control of HCV

描述：先天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），丙型肝炎病毒是一种阳性链RNA病毒，经常导致慢性肝炎、肝硬化和肝癌的持续感染。然而，关于肝细胞如何感知HCV感染并启动保护性反应，我们知之甚少。我们最近发现，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)，以识别病毒双链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。虽然rig - 1信号最近被证明有助于感知细胞内HCV RNA复制，但TLR3信号在HCV感染识别和控制中的作用仍有待确定，因为之前的研究都是在缺乏功能性TLR3通路的肝癌Huh7细胞中进行的。我们假设TLR3信号是一个重要的肝细胞抗病毒机制，并有助于宿主防御HCV。我们提出了该应用的三个目标：(1)确定TLR3的亚细胞定位和TLR3信号在肝细胞中的启动机制，以及它与RIG-I通路交叉对话的程度。(2)确定结构化的HCV RNA和HCV感染是否激活了TLR3重组Huh细胞中的TLR3信号通路，以及在支持HCV复制的细胞中，TLR3是否与HCV复制复合体相关。(3)确定TLR3信号是否参与肝细胞对HCV复制的控制。本研究将进一步加深我们对丙型肝炎发病机制中病毒-宿主相互作用的认识，以及先天免疫在控制丙型肝炎感染中的作用，这将有助于设计新的丙型肝炎感染治疗干预措施。

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.