Principal Investigator: Gerlinde Van de Walle

DESCRIPTION (provided by applicant): 

Equine parvovirus-hepatitis (EqPV-H) is the recently discovered cause of Theiler’s disease. It is a highly prevalent virus, affecting 3-12% of racehorses and up to 65% of broodmares on certain farms. Our preliminary data show that EqPV-H can result in a spectrum of clinical manifestations ranging from subclinical hepatitis to fatal hepatic necrosis, but the factors that determine disease severity are unknown. Two potential explanations for the differences in pathogenicity are (i) individual horse factors, such as immune response variation, and (ii) external risk factors that could precipitate enhanced viral replication and toxicity, such as hepatotoxin ingestion. We hypothesize that this second, “two-hit” model is highly likely because Theiler’s disease outbreaks often have multiple genetically unrelated animals all succumbing to disease within hours or days of each other.

While most parvoviruses preferentially infect rapidly dividing cells, a recently discovered human parvovirus uses the DNA damage response (DDR) pathway to replicate its viral genome in non-dividing cells. Hepatotoxins that induce DNA damage and/or promote a proliferative regeneration response might enhance parvoviral replication capacity and contribute to pathogenicity. Our data show that EqPV-H has a significant tropism for the liver and it is known that horses are frequently exposed to DNA-damaging hepatotoxins such as pyrrolizidine alkaloids. Additionally, EqPV-H-associated hepatic necrosis preferentially affects the centrilobular hepatocytes, which are typically non-dividing cells and highly susceptible to damage by hepatotoxins. Therefore, we hypothesize that EqPV-H uses the DDR pathway, instead of the cell replication machinery, to replicate and that DNA damage can enhance EqPV-H replication and pathogenesis.

Determining how EqPV-H replicates in the liver will provide a better understanding of the pathogenesis of this virus. This will be critical in the rational design of a safe and efficacious vaccine and in the identification of antiviral or therapeutic drugs for EqPV-H hepatitis, as well as to improve management strategies. Our studies are important to the racing industry because of the devastating economic impact of Theiler’s disease in broodmares and because of the potential that EqPV-H hepatitis negatively impacts race performance given the high prevalence in racehorses.