PROJECT SUMMARY The study of animal viruses has been critical for understanding basic disease mechanisms, including the origin and pathogenesis of related human viruses. In this proposal, two equine hepatitis viruses will be studied to elucidate mechanisms of viral hepatitis and the role of the immune system in pathology and viral clearance. Non-primate hepacivirus (NPHV) is the closest relative of hepatitis C virus, and horses are the primary host. A number of similarities between NPHV in horses and HCV in humans have been demonstrated, including liver tropism, the ability to cause persistent infection, delayed onset of immune responses coinciding with mildly increased liver enzymes, and a relatively large diversity among isolates. Equine Parvovirus-Hepatitis (EqPV-H) was recently discovered in a horse with serum hepatitis, also known as Theiler’s disease, and is currently considered the cause of that disease. Preliminary data demonstrate multiple similarities between EqPV-H in horses and parvovirus B19 in humans, including high prevalence in clinically healthy individuals, rare but important associations with fulminant hepatitis coincident with seroconversion, and persistence in the serum and tissues for years. Specific aims are to develop molecular and cell-based systems to study virus neutralization, entry, replication, and virion production, with the goals of contributing to measures preventing transmission and obtaining a deeper understanding of the molecular virology of these new viral hepatitis agents. In parallel, in vivo infections with NPHV and EqPV-H in horses will be used to elucidate their tropism, course and outcome of infection, immune responses, and pathology. Together, the findings of these studies have the potential to transform our understanding of the pathogenic mechanisms of viral hepatitis, to provide a model system for vaccine and/or therapeutic development, and to revolutionize veterinary medical practices to reduce or eliminate Theiler’s disease from horses. The proposed studies utilize the candidate’s unique qualifications as a Large Animal Internal Medicine specialist situated within a veterinary teaching and research institution. Career development plans will include mentoring from a team of highly qualified individuals, training in specific techniques of both in vitro and in vivo virology and immunology, and broader exposure to the fields of virology and immunology through University classes, seminars and journal clubs. The candidate intends to submit grants for further federal funding, including an R21 or R03 in the second year and an R01 in the final year, which will serve to achieve independence. This work ...