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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：
9064623
负责人：
KUI LI
金额：
$ 33.75万
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 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9064623
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 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 TLR3 gene TNFRSF5 gene Therapeutic Treatment Protocols Tropism Viral Virus Virus Replication Work base chemokine cohort cytokine genetic approach immune clearance improved interferon therapy intrahepatic liver biopsy liver inflammation novel p65 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）感染全球约1.3亿人，对人类健康构成重大威胁。HCV是一种嗜肝RNA病毒，在约70%的感染者中引起慢性肝脏炎症，使患者有肝硬化和肝细胞癌的危险。清除HCV感染需要发展强有力的和广泛的CD4和CD8 T细胞反应。不幸的是，这些反应经常失败，取而代之的是中间的细胞毒性T细胞反应，不能消除感染，但足以导致肝细胞破坏。对HCV的先天免疫反应提供了抵抗病毒的第一道防线，并且是协调后续T细胞反应的关键，但是它们如何在肝细胞中运作仍然知之甚少。我们最近的数据表明，人类肝细胞含有一个功能性toll样受体-3 （TLR3）信号通路，该信号通路感知HCV感染并导致促炎细胞因子和趋化因子的产生，这是将T细胞募集到肝脏的核心。然而，TLR3感知病毒复制过程中产生的HCV双链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在宿主对HCV的免疫反应中是至关重要的。因此，更好地了解这些分子事件对于提高我们对HCV宿主免疫反应和肝细胞中TLR3信号传导机制的认识至关重要，并为开发新型丙型肝炎免疫疗法奠定基础。目的1将确定在病毒复制过程中产生的HCV dsrna被内核体/溶酶体室中的TLR3感知的机制。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，并鉴定和表征在HCV感染期间被招募到内溶酶体以促进TLR3信号传导的细胞蛋白。Aim 2将描述HCV激活NF-kB并随后诱导促炎细胞因子和趋化因子的TLR3途径下游的信号机制。我们还将确定来自特定丙型肝炎患者队列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。

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The Type I IFN-Induced miRNA, miR-21.

DOI：
10.3390/ph8040836
发表时间：
2015-11-25
期刊：
Pharmaceuticals (Basel, Switzerland)
影响因子：
0
作者：
Yang CH;Li K;Pfeffer SR;Pfeffer LM
通讯作者：
Pfeffer LM

Thermal stability and inactivation of hepatitis C virus grown in cell culture.

DOI：
10.1186/1743-422x-7-40
发表时间：
2010-02-18
期刊：
Virology journal
影响因子：
4.8
作者：
Song H;Li J;Shi S;Yan L;Zhuang H;Li K
通讯作者：
Li K

Activation of chemokine and inflammatory cytokine response in hepatitis C virus-infected hepatocytes depends on Toll-like receptor 3 sensing of hepatitis C virus double-stranded RNA intermediates.

DOI：
10.1002/hep.24763
发表时间：
2012-03
期刊：
HEPATOLOGY
影响因子：
13.5
作者：
Li, Kui;Li, Nan L.;Wei, Dahai;Pfeffer, Susan R.;Fan, Meiyun;Pfeffer, Lawrence M.
通讯作者：
Pfeffer, Lawrence M.

Pivotal role for the ESCRT-II complex subunit EAP30/SNF8 in IRF3-dependent innate antiviral defense.