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

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 Own unpublished data could further demonstrate that HCV also interferes with the expression of the different growth factor receptor family members including the EGF receptor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