Infectious diseases account annually for almost a quarter of all human deaths worldwide. Against a constant background of established infections, epidemics of new and old infectious diseases periodically emerge, greatly magnifying the global burden of infections. Many pathogens causing disease in humans exhibit nearly unique human tropism, posing additional challenges for studying host-pathogen interactions and for testing intervention strategies. Our work focuses on identifying systematically barriers of interspecies transmission of human tropic pathogens and translating these discoveries into tractable experimental system allowing to dissect host responses to these diseases. My group combines molecular virology/pathogenesis, genetic screens, tissue and genome engineering to achieve these goals. We have successfully employed genetic host adaptation approaches to create the first humanized mouse models with inheritable susceptibility to hepatitis C virus infection. We now apply this strategy to overcome barriers for other major human pathogens, specifically hepatitis B and delta viruses. My lab has also pioneered xenotransplantation approaches to construct humanized mouse models for HIV and malaria. In particular human liver chimeric mice open unprecedented opportunities analyze host response to pathogens the physiologic 3D context of the liver.