Impact of parenchymal and nonparenchymal liver cells on Hepatitis B virus infection - Virus host interactions determine immunopathology and chronicity

• Applicant: Professorin Dr. Ruth Bröring
• Subject Area: Gastroenterology
• Term: from 2018 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 398762835

Chronic viral hepatitis caused by Hepatitis B virus (HBV) infection is among the most frequent causes for liver related morbidity and mortality. In recent years, it has become clear that not only the adaptive but also the innate immune system is involved in the pathogenesis of this infection. Pathogen recognition receptors, playing a central role in innate immunity, have recently been recognized to affect chronic viral hepatitis. However, HBV has evolutionarily evolved evading strategies to subvert the innate immune system of the liver, which is of relevance for understanding the mechanisms leading to chronicity of HBV infection. Immune evasion of HBV has been previously investigated in tumour cell lines transgenic for single viral proteins or infectious replication models, in vitro. Observation of immune evasion has also been found in HBV-infected humanized mice and chronically infected patients, in vivo. The HBV surface antigen (HBsAg) is a tolerogen that is supposed to dominate the immune evasion events. Aim of this proposal is the detailed description of intrahepatic immune control in HBV-transgenic mice, as a model for chronic HBV infection, focusing on molecular interactions between HBV and the hepatic environment represented by the major target cells (hepatocytes) and the immuno active non-parenchymal liver cells. The crucial question, how HBsAg affect the immunological function of these cells, and thereby control hepatic innate and adaptive immune responses, will be addressed using diverse HBV transgenic mouse strains, which differ in their hepatic phenotype. An HBsAg-deficient strain exhibit antiviral signaling, whereas Alb/HBs animals, that solely express HBsAg, show an inflammatory process. Interestingly, the HBsAg recovered strain, obtained by crossbreeding show a normal liver phenotype, indicating events of immune evasion. Comparisons between these models will allow drawing conclusions on HBsAg-dependent and HBsAg-independent immune evasion events, which will be mechanistically analyzed. One perspective of this work is the identification of specific HBV-induced serum markers that originate from the diverse liver cell types, allowing to individually rate the immunopathology of chronic HBV carriers. The expected findings will increase the knowledge on how HBV persists in chronically infected patients. These findings might lead to optimization of personalized treatment strategies.

• DFG Programme: Research Grants