Deciphering innate cellular immune responses that cause symptoms of hepatitis in a transgenic hepatitis B virus model

• Applicant: Professorin Dr. Ruth Bröring
• Subject Area: Gastroenterology
• Term: since 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 398762835

A major cause of liver-related morbidity and mortality is chronic hepatitis caused by hepatitis B virus (HBV) infection. While 95% of immunocompetent adults clear acute HBV infections spontaneously, persistent infections occur mainly in perinatal and childhood infections and in immunocompromised patients. Both the innate and adaptive immune systems are involved in the clearance of viral infections. The innate response is important for limiting viral replication in the early stages of infection and for orchestrating virus-specific adaptive immune responses, which have been shown to be necessary for clearance of HBV infection. In BR4014/5-1, we showed that the 1.4 overlength HBV s-rec mouse strain does not display a normal liver phenotype, as originally thought, but rather symptoms of mild hepatitis with elevated serum AST levels and reduced liver function. We found that HBV activates TLR2 and has the potential for antiviral cytokine responses in hepatocytes and Kupffer cells. Our results suggest that Kupffer cells and natural killer T cells are the possible causes of hepatitis symptoms in HBV transgenic mice lacking HBV-specific adaptive immunity. There is a close link between innate immunity and cellular metabolism, which allows adaptation to the demands of defence against infectious agents. However, HBV appears to be able to exploit these metabolic and immunogenic constraints to support its own replication. In the current proposal, light sheet fluorescence microscopy will be used to decipher the composition and function of the iMATE complexes seen in the tgHBV-s-rec and parental strains (Alb/HBs, tgHBV-s-mut), including KC phenotyping at sites of liver damage and along the lobular acinus. We will visualise the hepatic innate cellular network, consisting of Kupffer cells, NK/NKT cells and neutrophils in areas of liver damage, in viral hotspots in the context of lobular zonation in the phenotypically distinct HBV transgenic strains. The findings will be addressed mechanistically in autologous and allogeneic co-cultures. Finally, biomarkers that have the potential to be associated with hepatic innate forces against HBV will be investigated in murine and human serum samples. The relationship of these analytes to acute and chronic infection and to the different phases of chronic HBV infection will be addressed. Identification of innate immunity-related predictors for clearance of acute infection or seroconversion in chronic HBV carriers will be the ambitious goal.

• DFG Programme: Research Grants