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Interference of HCV with anti-infectious and inflammatory effector systems of the host

HCV对宿主抗感染和炎症效应系统的干扰

基本信息

批准号：
37394818
负责人：
Professor Dr. Johannes Georg Bode
金额：
--
依托单位：
Klinik für Gastroenterologie, Hepatologie und Infektiologie
依托单位国家：
德国
项目类别：
Research Units
财政年份：
2007
资助国家：
德国
起止时间：
2006-12-31 至 2014-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/37394818?language=en
关键词：
Interference HCV anti infectious inflammatory

项目摘要

The hepatitis C virus (HCV) develops persistent infections in over 60 % of cases implying that the virus has evolved strategies to influence the antiviral and inflammatory response of the host and to exploit the infrastructure of the host cell. During the current funding period we could show that HCV modifies Akt mediated growth factor signaling by NS3/4A dependent cleavage of the T-cell protein tyrosine phosphatase and that this as well as the tyrosine kinase c-Src is crucial for viral replication. Moreover, our data indicate that HCV or expression of the isolated NS3/4A protein influences basal and induced cytokine/chemokine expression in vitro and in vivo. This in turn might be responsible for the ameliorated course of LPS induced liver injury in NS3/4A transgenic animals. Based on these data the working hypothesis of the present project is that HCV disturbs NF-κB-, Akt- or p38MAPK dependent signal transduction of the host cell and hereby alters the basal as well as the inducible cytokine and chemokine expression pattern. This in turn would influence the surrounding liver tissue and in particular the differentiation state and number of immune competent cells such as monocytes, macrophages, dendritic cells, NK cells and the different T cell subtypes. The aim of the present project is to investigate the molecular mechanisms responsible for HCV dependent changes of basal and inducible chemokine expression and its impact on the migratory activity and differentiation of effector cells of the immune system, such as monocytes, macrophages and dendritic cells, the T cell subtypes and its influence on viral infectivity. In this context our observation that HCV induces degradation of different members of the inhibitor of kappa B family may be of particular relevance. The importance of these observations for HCV induced chemokine synthesis will be addressed as well as the underlying molecular mechanism responsible for HCV mediated degradation of the different IκB molecules. Furthermore the influence of HCV mediated TC-PTP suppression and enhancement of p38MAPK activity on the basal and cytokine induced chemokine production of hepatocytes will be assessed.

丙型肝炎病毒（HCV）在超过60%的病例中发展为持续感染，这意味着病毒已经进化出影响宿主的抗病毒和炎症反应并利用宿主细胞的基础结构的策略。在目前的资助期间，我们可以证明HCV通过NS 3/4A依赖性切割T细胞蛋白酪氨酸磷酸酶来修饰Akt介导的生长因子信号传导，并且这以及酪氨酸激酶c-Src对于病毒复制至关重要。此外，我们的数据表明，HCV或分离的NS 3/4A蛋白的表达影响基础和诱导的细胞因子/趋化因子在体外和体内的表达。这可能是NS 3/4A转基因动物LPS诱导的肝损伤过程改善的原因。基于这些数据，本项目的工作假设是HCV干扰宿主细胞的NF-κB-、Akt-或p38 MAPK依赖性信号转导，从而改变基础以及诱导型细胞因子和趋化因子表达模式。这进而会影响周围的肝组织，特别是免疫活性细胞如单核细胞、巨噬细胞、树突细胞、NK细胞和不同的T细胞亚型的分化状态和数量。本项目的目的是研究HCV依赖的基础和诱导型趋化因子表达变化的分子机制，及其对免疫系统效应细胞（如单核细胞、巨噬细胞和树突状细胞）的迁移活性和分化的影响，T细胞亚型及其对病毒感染性的影响。在这种情况下，我们观察到HCV诱导κ B家族抑制剂的不同成员降解可能特别相关。这些观察结果对HCV诱导的趋化因子合成的重要性以及HCV介导的不同IκB分子降解的潜在分子机制将得到解决。此外，将评估HCV介导的TC-PTP抑制和p38 MAPK活性增强对肝细胞的基础和细胞因子诱导的趋化因子产生的影响。