Research Focus
Viral infections of the liver are in most cases caused by one of the five hepatitis viruses: A. B, C, D and E. Although most infections are acute a self-limited, Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) infections can turn into chronic infection affecting 390 million people1. The decision whether infection develops into acute self-limiting or chronic infection is so far ill defined.
Our research focuses on the dynamics of antiviral immune responses against viral infections of the liver. We developed adenoviral infection models, mimicking hepatotropic infections, which can establish acute-self-limiting hepatitis as well as chronic infection of the liver. Using bioluminescence imaging, immunhistology and multiparametric flow cytometry we investigate in these models where antiviral CD8 T cell immunity is initiated and how CD8 T cells perform effector function in the liver. Knowledge obtained from these models are also currently transferred to HBV-infection models. Thereby, we monitor the priming and migration of HBV-specific CD8 T cells. Unraveling the dynamics of antiviral immune response will identify key mechanisms responsible for mounting a strong antiviral immunity towards HBV infection.
Recently we identified a new CD8 T effector cell (CTL) function which does not depend on the recognition of infected hepatocytes but rather on the recognition of antigen on cross-presenting liver sinusoidal endothelial cells (LSEC). Essential for this non-canonical CTL effector function is the secretion of TNF by these activated CD8 T effector cells which in turn selectively kills infected hepatocytes. The decision whether virus-infected hepatocytes die upon TNF receptor stimulation is made by the infected cells. We therefore investigate which molecules and pathways are involved in decision making and whether these decisions also sensitize infected hepatocytes towards other death inducing ligands. These pathways include intracellular caspase activation and signaling. Critical for regulation of caspase activity are, besides activation through the TNF receptor, mitochondria. We therefore developed methods to isolate and functional analyze mitochondrial activity and sensitivity towards intracellular death inducing pathways. Intracellular death receptor signaling is investigated for the established adenoviral infection as well as HBV-infection models.
This may help to understand the pathophysiological mechanisms leading on the one hand to elimination of viral infections and to hepatitis on the other hand. Ultimately, this may lead to the development of compounds/biologicals for preventing severe hepatitis after viral infection but allowing clearance of viral infection in chronic infections.
If you are interested to join our team we would be delighted to receive your application.
Funded by:
DFG: SFB TRR 179
