Chronic infection with the prototypic gamma-1 herpesvirus, Epstein-Barr Virus (EBV) in humans is usually asymptomatic, however, infection has been associated with lymphoid and epithelial malignancies in humans. The role of EBV in lymphomagenesis has been difficult to elucidate in part because concurrent genetic and environmental factors that influence viral pathogenesis such as spontaneous chromosomal translocations are difficult to accurately model in the research setting. Spontaneous lymphoma in the domestic dog comprises a large heterogeneous group of malignancies including Diffuse Large B Cell Lymphoma (DLBCL) and Burkitt-like lymphoma, that displaying similar genetic and cytogenetic changes to NHL subtypes in humans. Furthermore, the strong association between dog breed and predisposition to lymphoma indicates that genetic factors play a key role in determining susceptibility to lymphoma. Our preliminary data support and expand recent published findings that domestic dogs harbor an EBV-like gammaherpesvirus and that this may contribute to spontaneous lymphoma in this species. Taken together, these findings suggest that lymphomagenesis in dogs may have a viral etiology and recapitulate the complex interplay of genetic and epigenetic events associated with the viral pathogenesis of lymphoma in humans. In this exploratory proposal, we will explore the central hypothesis that pet dogs are infected with a gammaherpesvirus that has oncogenic potential. We will perform a prospective, longitudinal sero- epidemiological study to evaluate the association between viral infection and the development of B cell lymphoma in the Golden Retriever dog. Golden Retrievers are genetically predisposed to lymphoma and have an exceptionally high incidence of disease (incidence of 1 in 8 dogs). The limited genetic heterogeneity within the breed provides a unique opportunity to identify viral factors and genes that predispose to virus-associated lymphomagenesis in this species and we believe that this will have direct relevance to mechanisms promoting EBV-associated lymphomagenesis in humans. In addition, we aim to take advantage of our unlimited access to canine clinical tissue specimens and serum/plasma samples from dogs with spontaneous B cell lymphoma, to isolate and further characterize the canine EBV-like herpesvirus. We anticipate that our results will form the basis of a future R01 designed to investigate the role of this putative EBV-related herpesvirus in lymphomagenesis in dogs and establish the dog as a clinically relevant, spontaneous model to study viral- associated lymphomagenesis. If our hypothesis is correct, the results from the studies proposed here will have a significant impact on human health, identifying the dog as a clinically relevant, spontaneous, large animal model in which to identify factors influencing viral transformation and to test and advance virus targeted therapies in a pre-clinical setting.
Project narrative Chronic infection with Epstein-Barr Virus (EBV) is usually asymptomatic, however infection has been associated with lymphoid malignancies in humans. In this exploratory proposal we aim to study the association of natural infection with a novel oncogenic canine gammaherpesvirus with the development of lymphoma in the Golden Retriever dog that is genetically predisposed to lymphomagenesis. Development of this model of natural viral infection and spontaneous lymphomagenesis will allow us to evaluate genetic factors that influence viral pathogenesis and provide a clinically relevant large animal model that may be employed in the future to evaluate novel therapies for EBV-associated lymphoproliferative disorders in humans.