Equine herpesvirus 1 (EHV-1) is an alpha herpesvirus ubiquitous in horses worldwide. It initially infects the epithelium of the upper respiratory tract from where peripheral blood lymphocytes are infected that transport the virus to secondary sites of infection, including the spinal cord which results in crippling neurologic disease equine herpesvirus myeloencephalopathy (EHM). Immunity following vaccination or primary infection is incomplete and unable to protect against reinfection and development of disease. The long term objective of the described work is to identify and target pathways involved in EHM pathogenesis in order to prevent disease. Due to the complex interplay between viral immune-modulating features as well as host immunity, understanding protection from EHM following EHV-1 infections remains elusive. This dissertation is aimed at providing clarity to ultimately understand how EHV-1 immunity can be altered in order to offer more complete protection. We conducted an evolving assortment of in vitro and in vivo experiments investigating differing aspects of EHV-1 infection and immunity at key sites of infection including the respiratory epithelium and peripheral blood lymphocytes. As the site of first contact and viral replication, the respiratory epithelium is the site where the first innate immune responses occur which dictates the phenotype and success of downstream adaptive immunity. As such, in Chapters 2 and 3 I describe experiments to interfere with viral replication and boost host immunity in the respiratory epithelium. Chapters 4 and 5 discuss in-depth transcriptomic analyses to investigate the systemic host immune response as well as viral and host gene expression in peripheral blood cells during peak EHV-1 viremia and EHM disease.
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