Immune system-independent mechanisms of hepatic pathogenesis and carcinogenesis in Schistosoma mansoni/hepatitis B virus co-infection

• Applicants: Professor Dr. Dieter Glebe; Privatdozent Martin Roderfeld, Ph.D.
• Subject Area: Gastroenterology
• Term: since 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 423812391

Chronic stages of schistosomiasis and HBV occur disproportionately often as co-infections in endemic areas. A previous infection with S. mansoni is suspected to predispose for infections with hepatitis B virus (HBV) and hepatitis C virus (HCV). Co-infections of HBV and S. mansoni also accelerate liver disease progression, increase mortality through an enhanced incidence of liver cirrhosis and HCC. Molecular mechanisms of endogenous damage to the host parenchyma by e.g. hepatocellular stress, fibrosis, and carcinogenesis during co-infection have not been addressed so far, although they very likely play a role in disease progression, as our preliminary work on HBV- and schistosomiasis-induced liver pathogenesis suggests. Based on clinical studies on S. mansoni/HBV co-infection and our preliminary work, we aim to analyze how immune system-independent mechanisms are involved in hepatic pathogenesis and carcinogenesis. Since the available clinical data suggest that a previous infection with S. mansoni can promote hepatocellular carcinogenesis, this point should also be addressed. With the present project, we aim to characterize pathological mechanisms of a concurrent and previous infection of S. mansoni in HBV models. Hypothesis 1: S. mansoni-induced metabolic stress and HBV surface protein-induced endoplasmic stress in hepatocytes synergistically amplify resulting liver parenchyma damage and carcinogenesis. In the murine HBV model, molecular-biological principles of hepatic parenchyma damage in components of a S. mansoni co-infection are to be determined. Mechanistic relationships of the pathogenesis as well as diagnostic and therapeutic options are analyzed in gain-and-loss-of-function experiments. Hypothesis 2: A successfully treated previous infection with S. mansoni increases the incidence and aggressiveness of hepatocellular carcinogenesis in the HBV mouse model. In regions where schistosomiasis is endemic, more than 200 million people are treated prophylactically with praziquantel each year, which kills the worms but not the eggs of the parasite. In the HBV mouse model, liver damage caused by persistent parasite eggs after a successfully treated S. mansoni co-infection is to be analyzed. In gain-and-loss-of-function experiments, mechanistic relationships of the pathogenesis as well as diagnostic and therapeutic options are analyzed. The results from the models of both TPs are to be validated using primary human hepatocytes and human reference samples.

• DFG Programme: Research Grants
• Co-Investigator: Professorin Dr. Elke Roeb