Role of TLR3 Signaling in Control of HCV

TLR3 信号传导在 HCV 控制中的作用

• 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
• 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

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）在全球大约感染了约1.3亿人，并对人类健康构成了重大威胁。 HCV是一种肝转播RNA病毒，在约70％的感染个体中引起慢性肝发炎，使患者处于肝硬化和肝细胞癌的风险。 HCV感染的清除需要剧烈和广泛的CD4和CD8 T细胞反应的发展。不幸的是，这些反应通常会失败，并用中间的细胞毒性T细胞反应取代，无法消除感染，但足够强，可以引起肝细胞破坏。对HCV的先天免疫反应提供了针对该病毒的第一道防线，并且对于策划随后的T细胞反应至关重要，但是它们在肝细胞中的运作方式仍然很差。我们最近的数据表明，人肝细胞包含一种功能性Toll样受体-3（TLR3）信号传导途径，该信号传导途径感受到HCV感染并导致产生促炎性细胞因子和趋化因子，这是将T细胞募集到肝脏的核心。然而，TLR3在病毒复制过程中产生的HCV双链（DS）RNA的机制尚不清楚NF-KB激活和随后诱导促炎介质的诱导。我们假设HCV-Hepatocyte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，对这些分子事件的更好理解对于促进我们对宿主免疫反应的知识以及肝细胞中TLR3信号传导的机制至关重要，并为开发乙型肝炎的新型免疫治疗奠定了基础。 AIM 1将确定TLR3在内体/溶酶体区室中检测到在病毒复制过程中产生的HCV DSRNA的机制。我们将描述自噬在TLR3依赖性宿主对HCV感染的反应中的作用，并识别和表征募集到内溶性溶肿的细胞蛋白，以促进HCV感染期间TLR3信号传导。 AIM 2将表征TLR3途径下游的信号传导机制，HCV激活NF-KB并随后诱导促炎细胞因子和趋化因子。我们还将确定来自特定的丙型肝炎患者队列的诊断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，并定义了它们与肝炎症的可能关系。