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）感染导致持续感染的发展。这导致HCV感染是全球慢性肝病的主要原因。尽管病毒颗粒持续复制和产生，但多年的寡发病或无症状疾病的爬行过程意味着病毒已经进化出影响宿主的抗病毒和炎症反应的策略，并在不影响其活力的情况下利用宿主细胞基础结构。本课题组的前期工作表明，HCV可使其宿主细胞对表皮生长因子（EGF）敏感，并增强EGF诱导的细胞内信号转导。未发表的数据可以进一步证明，HCV也干扰不同生长因子受体家族成员的表达，包括EGF受体（EGFR）ErbB2至4。因此，HCV上调ErbB3配体Neuregulin（NRG）1的表达，其进而在转录物和蛋白质水平介导ErbB3表达的下调。ErbB3的这种下调伴随着EGFR和ErbB2的表面表达增强。这些变化可能与令人惊讶的观察结果有关，即HCV感染导致EGF表达增强，扩展了EGF靶基因的谱，并将EGF转化为趋化因子表达的有效诱导剂。很可能，这与EGF受体对EGF的敏化作用一起导致HCV影响其宿主细胞的细胞间通讯和功能以及可能影响其自身生命周期的环。基于这些观察，本项目的目的是A）阐明HCV诱导NRG 1和EGF表达的分子机制，以及B）表征参与其自身配体NRG 1控制ErbB 3表达的途径。此外，该项目将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，D）HCV干扰生长因子及其同源受体的表达和信号转导对其宿主细胞的细胞间通讯及其自身生命周期的功能后果将进一步详细研究。预计拟议的工作包的结果不仅提供信息的影响，丙型肝炎病毒对内和细胞间的信号传导的主机，但也揭示了新的见解的信号传导途径，控制生长因子的基因表达和生长因子的机制控制自己的受体的表达。

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 Own unpublished data could further demonstrate that HCV also interferes with the expression of the different growth factor receptor family members including the EGF receptor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.