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Abstract
Virus-host interactions determine the outcome of the infection. Resistance to and recovery from a viral infection depends upon the efficiency by which the immune system inhibits viral spread. Most viruses encode factors to suppress the innate immune response. Bovine Herpesvirus-1 (BHV-1) infects cattle and similar to other alphaherpesvirinae subfamily members, establishes latency in sensory neurons. During acute infection and establishment of latency, BHV-1 viral genes interact with various cellular factors and repress the immune responses. One of the immediate early proteins, bICP0 has been identified as a viral component that suppresses innate immune responses. bICP0 can transactivate all viral promoters, and as such stimulates productive infection. Consequently, I have hypothesized that bICP0 has two functions that are crucial for stimulating productive infection: blocking of interferon signaling and activation of viral transcription. This hypothesis is the basis of my dissertation research.
The zinc RING finger and transactivation domains within bICP0 are believed to contribute significantly to the functions of bICP0. I have demonstrated that the bICP0 C-terminus domains are required for inhibiting IFN-β promoter activation. The C-terminus domains and the zinc RING finger are required for degrading interferon regulatory factor 3 (IRF3), a transcription factor involved in Type I IFN expression. The studies also suggest that bICP0 binds to interferon regulatory factor 7 (IRF7) and thus prevents it from activating the IFN-β promoter. Collectively these studies indicate that bICP0 disarms the innate immune response by targeting the transcription factors IRF3 and IRF7. To understand the role of zinc RING finger in productive infection, I generated a bICP0 zinc RING finger mutant BHV-1 virus. The mutant virus was characterized in cultured bovine cells and calves. In cell culture, the mutant virus has delayed growth as compared to the wild type or rescued virus. Similarly in calves, the mutant virus did not replicate as efficiently as the rescued virus and the immune response was also reduced. I believe these studies provide valuable information with respect to understanding BHV-1 pathogenesis, and the role that the zinc RING finger plays in virus-host interactions.
