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：
8435728
负责人：
KUI LI
金额：
$ 28.2万
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 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8435728
关键词：
Acute Adverse effects Affect Antiviral Therapy Autophagocytosis Biopsy Specimen CD8B1 gene Cell membrane Chronic Chronic Hepatitis C Cirrhosis Clinical Complex Cytotoxic T-Lymphocytes Data Development Diagnostic Disease Double-Stranded RNA Endosomes Event FDA approved Family Flaviviridae Foundations Genetic Genotype Health Hepatic Hepatitis C Hepatitis C virus Hepatocyte Human Immune Immune response Immunotherapy Individual Infection Inflammation Inflammatory Response Injury Interferons Knowledge Lead Life Liver Lysosomes Mediating Mediator of activation protein Molecular NF-kappa B Pathway interactions Patients Phase Poly I-C Primary carcinoma of the liver cells Production Protease Inhibitor Proteins RNA Viruses Recruitment Activity Resistance Risk Role Signal Pathway Signal Transduction Signaling Molecule T cell response T-Lymphocyte TNFRSF5 gene Therapeutic Treatment Protocols Tropism Viral Virus Work base chemokine cohort cytokine human TLR3 protein immune clearance improved interferon therapy intrahepatic liver biopsy liver inflammation novel p65 public health relevance response

项目摘要

DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) infects approximately 130 million people worldwide and poses a major threat to human health. HCV is a hepatotropic RNA virus that causes chronic hepatic inflammation in ~70% of infected individuals, putting patients at risk for cirrhosis and hepatocellular carcinoma. Clearance of HCV infection requires the development of vigorous and broad CD4 and CD8 T cell responses. Unfortunately, these responses often fail and are substituted with an intermediate cytotoxic T cell response unable to eliminate the infection but strong enough to cause hepatocyte destruction. The innate immune responses to HCV provide the first line of defense against the virus and are pivotal for orchestrating subsequent T cell responses, but how they operate in hepatocytes remains poorly understood. Our recent data suggest that human hepatocytes contain a functional Toll-like receptor-3 (TLR3) signaling pathway that senses HCV infection and leads to production of proinflammatory cytokines and chemokines which are central to recruiting T cells to the liver. However, the mechanisms by which TLR3 senses HCV double-stranded (ds) RNAs generated during viral replication and results in NF-kB activation and subsequent induction of proinflammatory mediators are unclear. We hypothesize that these molecular events in HCV-hepatocyte interactions are crucial in host immune responses to HCV. Therefore a better understanding of these molecular events is crucial for advancing our knowledge on host immune responses to HCV and the mechanisms of TLR3 signaling in hepatocytes, and lays the foundation for developing novel immunotherapies for hepatitis C. The work proposed involves two specific aims. Aim 1 will determine the mechanism by which HCV dsRNAs generated during viral replication are sensed by TLR3 in endosome/lysosome compartments. We will delineate the role of autophagy in TLR3- dependent host response to HCV infection, and identify and characterize cellular proteins that are recruited to endolysosomes to facilitate TLR3 signaling during HCV infection. Aim 2 will characterize the signaling mechanisms downstream of the TLR3 pathway by which HCV activates NF-kB and subsequent induction of proinflammatory cytokines and chemokines. We will also determine the expression of selected innate immune signaling molecules and proinflammatory mediators in diagnostic liver biopsy specimens from a specific cohort of hepatitis C patients and define their possible relationship to hepatic inflammation.

描述（由申请人提供）：丙型肝炎病毒（HCV）感染全世界约 1.3 亿人，对人类健康构成重大威胁。 HCV 是一种亲肝 RNA 病毒，可导致约 70% 的感染者出现慢性肝脏炎症，使患者面临肝硬化和肝细胞癌的风险。清除 HCV 感染需要产生活跃且广泛的 CD4 和 CD8 T 细胞反应。不幸的是，这些反应常常失败，并被中间细胞毒性 T 细胞反应所取代，该反应无法消除感染，但强度足以导致肝细胞破坏。针对 HCV 的先天免疫反应提供了针对病毒的第一道防线，并且对于协调后续 T 细胞反应至关重要，但它们如何在肝细胞中发挥作用仍知之甚少。我们最近的数据表明，人类肝细胞含有功能性 Toll 样受体 3 (TLR3) 信号通路，该通路可感知 HCV 感染并导致促炎细胞因子和趋化因子的产生，这对于将 T 细胞招募到肝脏至关重要。然而，TLR3 感知病毒复制过程中产生的 HCV 双链 (ds) RNA 并导致 NF-kB 激活和随后诱导促炎介质的机制尚不清楚。我们假设 HCV-肝细胞相互作用中的这些分子事件对于宿主对 HCV 的免疫反应至关重要。因此，更好地了解这些分子事件对于增进我们对 HCV 宿主免疫反应和肝细胞中 TLR3 信号转导机制的了解至关重要，并为开发丙型肝炎新型免疫疗法奠定基础。拟议的工作涉及两个具体目标。目标 1 将确定病毒复制过程中产生的 HCV dsRNA 被内体/溶酶体区室中的 TLR3 感知的机制。我们将描述自噬在 HCV 感染的 TLR3 依赖性宿主反应中的作用，并鉴定和表征被招募到内溶酶体以促进 HCV 感染期间 TLR3 信号传导的细胞蛋白。目标 2 将描述 TLR3 通路下游的信号传导机制，HCV 通过该通路激活 NF-kB 并随后诱导促炎细胞因子和趋化因子。我们还将确定特定丙型肝炎患者的诊断性肝活检标本中选定的先天免疫信号分子和促炎介质的表达，并确定它们与肝脏炎症的可能关系。