Major Research Interests:
Gene regulation and innate immune response of two Alphaherpesviruses equine herpesvirus 1 (EHV-1) and varicella-zoster virus (VZV)
Equine herpesvirus 1 (EHV-1) is an important pathogen of equines and a useful model to investigate Alphaherpesvirus gene regulation as its gene program is initiated by a single immediate-early protein (IEP) which activates expression of >50 early (E) genes. The IEP possesses several domains essential for trans-activation, including an acidic trans-activation domain (TAD) and binding domains for DNA and general transcription factors. However, the mechanism by which the IEP TAD functions in activating transcription remains unknown. We hypothesize that the IEP interacts with TBP, TFIIB, and TFIIA, and that its TAD mediates gene expression by recruiting components of the RNA polymerase II machinery, such as Mediators and TBP-associated factors (TAFs). We are also interested in understanding the protective mechanisms elicited by attenuated EHV-1 KyA in CBA mice. EHV-1 KyA immunization effectively protected CBA mice from pathogenic RacL11 challenge by inducing the expression of the IFN-γ gene and 16 interferon-stimulated genes (ISGs). These results suggest that KyA is a strong candidate as a live attenuated EHV-1 vaccine in horses. Evaluation of each ISGs expressed in recombinant Adenovirus will identify the ISG(s) with maximal antiviral activity and allow experiments to define its mechanism of antiviral function. These findings may reveal new and novel targets to inhibit herpesvirus replication.
Varicella-zoster virus (VZV) is a ubiquitous human pathogen that establishes latency in sensory ganglia; upon reactivation, the virus migrates to the skin via axonal transport to cause zoster (shingles). IFN-γ is a potent cytokine produced following primary VZV infection. How VZV overcomes this cutaneous IFN-γ barrier and produces skin vesicles is not known. Our results showed that IFN-γ effectively inhibited VZV replication and immediate-early 62 protein (IE62)-mediated trans-activation in lung epithelial A549 and retinal epithelial ARPE-19 cells but not in skin melanoma MeWo cells. IE62, a major viral trans-activator, initiates the virus life cycle and is a key component of pathogenesis. These results led us to hypothesize that IFN-γ blocks VZV replication by inhibiting IE62 function. Functional mechanisms of IFN-γ in VZV replication could provide important information to control VZV replication and pathogenesis, but also identify factors contributing to the tissue restriction of VZV.
