Regulation of Bovine Herpesvirus 1 (BHV-1) Productive Infection by Cellular Transcription Factors

Bovine herpesvirus 1 (BHV-1) is a significant viral pathogen of cattle responsible for a variety of disease conditions, including: conjunctivitis, pneumonia, genital disorders, abortions, and shipping fever, a serious upper respiratory tract infection. Following acute infection in mucosal epithelium, BHV-1 establishes a lifelong latent infection in sensory ganglionic neurons. During latency, transcription is restricted to the latency related (LR) gene. Elevated corticosteroid levels due to stress and/or immune suppression can initiate reactivation from latency, resulting in virus shedding and spread to susceptible cattle. Additionally, administration of dexamethasone (Dex), a synthetic corticosteroid, to calves latently infected with BHV-1 reproducibly leads to reactivation from latency. During reactivation, productive viral gene expression is readily detected in sensory neurons, LR gene expression decreases, and infectious virus is secreted. However, as with other alpha-herpesviruses, the molecular mechanisms that occur during successful reactivation from latency are poorly understood. Therefore, this dissertation was aimed at the elucidation of the early events of the latency-reactivation cycle of alpha-herpesviruses. Furthermore, the aim was to reveal the function of cellular transcription factors in the latency-reactivation cycle. Since BHV-1 is the only alphaherpesvirinae subfamily member that can be reproducibly induced to reactivate from latency, we were also interested in examining the effect of these cellular factors on other important members of this virus family. Collectively, studies presented in this dissertation characterized several cellular transcription factors that are induced in the trigeminal ganglia of latently infected cattle following treatment with Dex to induce reactivation from latency. These cellular transcription factors activate viral transcription and stimulate BHV-1 productive infection in cultured cells, suggesting they may facilitate the exit from latency. A subset of these cellular factors also regulates herpes simplex virus 1 (HSV-1) productive infection and/or promoter activity. Therefore, based on the data presented in this dissertation, we hypothesize that stressful stimuli promotes the exit from latency by activating specific cellular transcription factors, which consequently activate lytic viral gene expression and production of infectious virus. Advisor: Clinton Jone