Interference of HCV with growth factor production and signalling - molecular mechanisms and functional consequences.

在超过60%的病例中，丙型肝炎病毒(HCV)感染会导致持续感染。这导致了丙型肝炎病毒感染是全球慢性肝病的一个主要原因。尽管病毒颗粒持续复制和产生，但多年的寡发性或无症状疾病的缓慢过程表明，病毒已经进化出影响宿主的抗病毒和炎症反应的策略，并在不影响其生存能力的情况下利用宿主细胞基础设施。本课题组以前的工作表明，丙型肝炎病毒使其宿主细胞对表皮生长因子(EGF)敏感，并增强由EGF引发的细胞内信号转导。自身未发表的数据进一步表明，丙型肝炎病毒还干扰不同的生长因子受体家族成员的表达，包括表皮生长因子受体(EGFR)ErbB2到4。因此，丙型肝炎病毒上调ErbB3配体神经调节蛋白(NRG)1的表达，进而在转录和蛋白水平上介导ErbB3表达的下调。这种ErbB3的下调伴随着EGFR和ErbB2表面表达的增强。这些变化很可能与令人惊讶的观察结果有关，即丙型肝炎病毒感染导致EGF表达增强，扩大了EGF靶基因的范围，并将EGF转化为有效的趋化因子表达诱导剂。可以想象，这与EGF受体对EGF的敏感性一起导致了一个循环，通过这个循环，丙型肝炎病毒影响其宿主细胞的细胞间通信和功能，也可能影响其自身的生命周期。基于这些观察结果，本项目的目的是：1)阐明丙型肝炎病毒诱导NRG1和EGF表达的分子机制；2)研究其自身配体NRG1调控ErbB3表达的途径。此外，该项目将C)系统地分析这些变化对ErbB受体家族其他成员表面表达的影响。最后，将进一步详细研究丙型肝炎病毒干扰生长因子及其同源受体的表达和信号转导对宿主细胞间通讯和自身生命周期的功能影响。预计拟议工作包的结果不仅提供了关于丙型肝炎病毒对宿主细胞内和细胞间信号传递的影响的信息，还揭示了控制生长因子基因表达的信号通路以及生长因子控制其自身受体表达的机制的新见解。

In over 60% of cases infection with the hepatitis C virus (HCV) results in the development of persistent infection. This contributes to the fact that HCV infection is a major cause of chronic liver diseases worldwide. The creeping course with years of oligo- or asymptomatic disease in spite of persistent replication and production of viral particles implies that the virus has evolved strategies to influence the antiviral and inflammatory response of the host and to exploit the host cell infrastructure without affecting its viability. Previous work of our group could demonstrate that HCV sensitizes its host cell for epidermal growth factor (EGF) and enhances the intra-cellular signal-transduction elicited by EGF. Own unpublished data could further demonstrate that HCV also interferes with the expression of the different growth factor receptor family members including the EGF receptor (EGFR) ErbB2 to 4. Thereby, HCV up-regulates the expression of the ErbB3 ligand Neuregulin (NRG)1, which in turn mediates down-regulation of ErbB3 expression at transcript and protein level. This down-regulation of ErbB3 is accompanied by an enhanced surface expression of EGFR and ErbB2. It is likely that these changes are linked to the surprising observation that HCV infection results in an enhanced EGF expression, extends the spectrum of EGF target genes and converts EGF into a potent inducer of chemokine expression. It is well conceivable that this together with the sensitization of the EGF receptor towards EGF results in a loop by which HCV influences the intercellular communication and function of its host cell and possibly also its own life cycle. Based on these observations the present project aims to A) elucidate the molecular mechanisms by which HCV induces expression of NRG1 and EGF and to B) characterize the pathways that are involved in the control of ErbB3 expression by its own ligand NRG1. Moreover, the project will C) systematically analyse the consequences of these changes for the surface expression of the other members of the ErbB receptor family. Finally, D) the functional consequences of the interference of HCV with the expression and signal-transduction of growth factors and their cognate receptors for the intercellular communication of its host cell and for its own life cycle will be investigated in further detail. It is expected that the results of the proposed work packages not only provide information on the influence of HCV on intra- and inter-cellular signalling of its host but also reveals novel insights in the signalling pathways that controls the gene expression of growth factors and the mechanisms by which growth factors control the expression of their own receptors.