Mechanisms of parvovirus replication in viral hepatitis

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Project Summary The study of animal viruses has been critical for understanding basic disease mechanisms, including the pathogenesis of related human viruses. This Mentored Clinical Scientist Research Career Development Award proposal presents a five-year research program to study the mechanisms by which a novel parvovirus successfully replicates in terminally differentiated hepatocytes. Equine parvovirus-Hepatitis (EqPV-H), a novel Copiparvovirus, is known to cause hepatitis and fulminant hepatic necrosis in horses. Preliminary data demonstrate multiple similarities between EqPV-H in horses and parvovirus B19 in humans, including high prevalence in clinically healthy individuals and rare but important associations with fulminant hepatitis. Parvoviruses utilize either the host cell replication machinery or the DNA damage response (DDR) pathway to replicate their viral genomes. The foundation for this proposal is based on studies evaluating the cellular division status of hepatocytes infected with EqPV-H following experimental inoculation in vivo that suggest that cells with viral replication are most commonly in G0 phase of the cell cycle. This proposal will address the following specific aims: Aim 1) Determine the cellular division and DNA damage response (DDR) status of EqPV-H-infected hepatocytes and association with pathology in situ; Aim 2) Evaluate the impact of DNA damage-induced DDR activation and DDR inhibition on EqPV-H replication and hepatotoxicity in vitro; and Aim 3) Determine the role of host cell polymerases in EqPV-H replication in vitro. These aims align with Dr. Jager’s career development goals: 1) Training in cell culture development and optimization; 2) Training in molecular virology, cell biology, and toxicology; and 3) Training in confocal microscopy and spatial transcriptomics. To achieve these goals, Dr. Jager has assembled a highly qualified team of mentors including: his primary mentor, Dr. Gerlinde Van de Walle, a veterinary clinician-basic scientist with expertise in viral pathogenesis and development of novel cell culture systems; co-mentor Dr. Colin Parrish, a skilled molecular virologist with extensive parvovirus research experience; and co-mentor Dr. Robert Weiss with expertise in the DDR pathway. Additionally, the team includes collaborators with expertise in parvoviral replication dynamics, hepatopathology, and equine parvovirus. The candidate plans to submit grants for further federal funding, including an R21 or R01 in the fourth year, with the goal of achieving independence. This K08 award will allow Dr. Jager to develop a sub-specialty in hepatopathology and viral pathogenesis that will help launch his academic career as an independent clinician- scientist.