Virus-induced changes in cellular signaling in hepatocytes lead to reprogramming of the cell response to growth factors – analysis of molecular mechanisms and functional consequences

• Applicant: Professor Dr. Johannes Georg Bode
• Subject Area: Gastroenterology ; Immunology ; Virology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 509068088

In previous work, we were able to contribute to a better understanding of the mechanisms by which viral pathogens, such as hepatitis C virus (HCV) or cytomegalovirus, interact with the intra- and intercellular signal transduction of the host. These studies led not only to new insights into virus-host interaction but also into signal transduction in the host and the effects of altering the activation of signaling intermediates on the overall signaling network. For example, proteolytic degradation of ubiquitously expressed T-cell protein tyrosine phosphatase (TC-PTP), an important endogenous negative regulator of the EGF receptor, by the virus-encoded protease NS3/4A leads not only to enhanced activability of the EGF receptor but also to constitutive activation of protein kinase Akt. This suggests that TC-PTP indirectly controls Akt kinase activation. Further, we demonstrated that this contributes substantially to "reprogramming" of the host cell in its response to ErbB ligands. For example, HCV elicits an extensive change in the surface expression of members of the ErbB receptor family and leads to the induction of the expression of several ErbB ligands such as EGF, neuregulin-1, and heregulin, some of which in turn activate auto-regulatory feedback mechanisms. This culminates in a significant change in the chemokine-mediated inter-cellular communication behavior of the host cell. Mechanisms that are essential contributors to the development of insidious, but not abating, liver inflammation characterized by a variety of changes in the local immune or microenvironment. Since approximately 90% of HCC cases develop in the context of chronic liver inflammation, it is reasonable to speculate that the ongoing inflammatory response associated with hepatocyte "reprogramming“ investigated herein also plays an important role in the malignant transformation of liver cells in the context of chronic inflammatory responses. In this study we would like to further elucidate the molecular mechanisms by which hepatitis viruses such as HBV and HCV influence the regulation of the expression of ErbB ligands in hepatocytic cells. Furthermore, the reciprocal effects of the induction of these different ErbB ligands on the surface expression of ErbB receptor family members in the host cell and the importance of the dysregulation or enhanced activation of the transcription factors SP1 and NFkB will be further investigated. Finally, the impact of this host cell reprogramming on intercellular communication with and function of immune cells such as monocyte-derived macrophages will be investigated and signals relevant in this context identified.

• DFG Programme: Research Grants