Bovine herpesvirus type 1 (BHV-1) regulates the innate immune system to promote productive infection and latency

Bovine herpesvirus type 1 (BHV-1) is a significant viral pathogen of cattle that is responsible for a variety of disease conditions, including conjunctivitis, genital disorders, abortions, and upper respiratory tract infection, known as infectious bovine rhinotracheitis (IBR). BHV-1 infection can also lead to transient immune-suppression and predispose cattle to secondary bacterial infection. Consequently, life-threatening pneumonia can occur and this is referred to as bovine respiratory disease (BRD). During acute infection, approximately 73 viral genes are expressed in a well defined cascade. Following acute infection in mucosal epithelium, BHV-1 establishes a life-long latency in sensory ganglionic neurons. During latency, viral gene expression is restricted to the latency related (LR) gene. The LR gene encodes proteins and noncoding small RNAs that promote latency. My dissertation has focused on investigating the mechanisms by which BHV-1 regulates the innate immune responses during acute infection and latency. This study initially characterized the promoters that control the expression of the three bovine interferon beta (IFN-β) genes in response to viral infection and virus induced transcription factors in several cell types. These studies demonstrated that BHV-1 infection suppresses the IFN-β response in low passage bovine cells. Two BHV-1-encoded genes: bovine infected cell protein 0 (bICP0) and bICP27 were found to suppress the transcriptional activity of the bovine IFN-β gene promoters. The viral protein bICP0 inhibited IFN-β signaling in the cytoplasm. In contrast, bICP27 required nuclear localization to interfere with IFN-β signaling. Studies demonstrating that BHV-1 may subvert the innate immune system in order to promote latency were also conducted. For example, two miRNAs encoded by the LR gene were shown to interfere with RIG-I to stimulate the IFN-β response and NF-κB-dependent transcription, which correlated with increased cell survival. Collectively, these studies suggest that: (i) BHV-1 suppresses the innate immunity in order to establish an efficient productive infection, and (ii) the LR gene-encoded miRNAs subvert the innate immune system to promote an environment that is favorable for the establishment and/or maintenance of latency