Chronic hepatotropic infections including hepatitis B (HBV) and C (HCV) are a major public health concern. Even though both viruses belong to completely distinct families the pathogenesis they elicit is strikingly similar, leading to liver fibrosis and cirrhosis. Treatment for HBV and HCV consists of either direct-acting antivirals or pegylated interferon (IFN)α. In contrast to HCV, these treatment regimen are noncurative for HBV. Little is known to date about the host/pathogen interactions determining viral persistence.Both viruses are sensitive to IFN, activating the JAK/STAT signalling pathway to activate interferonstimulated gene expression (ISG), which are ultimately acting as antiviral immune effectors. Nevertheless, neither type I or III IFN are very effective in their treatment.Here, we suggest investigating the mechanistic details of type I and type III IFN action on HCV andHBV in vitro and vivo with the goal of uncovering not only the differential ISG induction but furthermore characterise viral immune evasion strategies. Building on our previous success in dissecting the host response to HCV and creating the first immunocompetent mouse model for HCV we aim at using both, novel microfluidic culture systems based on 3D hepatocyte cultures susceptible to both HCV and HBV as well as human liver-chimeric mice in combination with single-cell analysis of the antiviral response against HBV and HCV elicited by type I and III IFN. Additionally, we will utilize lentiviral high throughput screening used previously for HCV to identify interferon effector molecules active against HBV. This project will not only provide new insights into the innate immune response to chronic hepatotropic virus infections but furthermore holds the potential of uncovering novel drug targets, aiding in the curative therapy for both, HCV and HBV and offer novel insights into vaccine design.This project has the aim of identifying novel host factors and drug targets enabling the development of immunomodulatory antiviral drugs. This ranks the scope of the proposal between LS6 Immunity and Infection and LS9 Applied Life Sciences and Non-Medical Biotechnology. Evaluating novel bioengineered human liver culture systems and building on human liver-chimeric mice clearly places this proposal at the forefront of identifying novel drug targets and assisting in the development of novel biotechnology and preclinical projects.