Herpesviruses establish a life-long infection in their hosts. Ultimately, each herpesvirus has evolved an intricate strategy of manipulating the host cells and host immune response to support its complex life cycle that involves: (1) replication and expansion, (2) dissemination to reservoirs where the virus establishes a latent (quiescent infection), (3) maintenance of latency to persist in the host, (4) evasion of immune clearance, and (5) reactivation to produce infectious particles that seed new cells and new hosts.
The latent program of the gammaherpesviruses Epstein-Barr Virus (EBV) and Kaposi’s sarcoma associated-herpesvirus (KSHV) in cellular reservoirs is associated with lymphomas and neoplasms.
My research interests lie in understanding the molecular determinants of virus-host interactions during chronic gammaherpesvirus infections. We seek to dissect this complex virus and host interplay using a model pathogen system to find novel therapeutics.
Murine gammaherpesvirus 68 (MHV68) is a natural pathogen of mice. MHV68 has genetic colinearity and biological parallels with its human counterparts. The ease of generating recombinant MHV68 viruses coupled with the availability of genetically altered mice provides a tractable model system to identify and characterize virus and host determinants of chronic infection. In addition, we can further define the molecular mechanisms of these determinants in lytic and latent cell culture systems.
We have several projects in our laboratory.
1. Host signaling pathways can determine whether a gammaherpesvirus establishes a latent infection or undergoes productive replication. We are evaluating the consequence of upstream signaling events and the downstream activation of NF-κB and STAT3 transcription factors on the regulation of viral and host genes.
2. All herpesviruses encode a uracil DNA glycosylase (UNG). It is unclear how uracil incorporation impacts replication and if the viral UNG counteracts host cytidine deaminase activity. We are interested in the role of the viral UNG in gammaherpesvirus replication and pathogenesis in particular cell-types and tissues.
3. The tegument of herpes virus particles can deliver pre-formed proteins to a newly infected cell. We are seeking to understand how the tegument impact early infection events. All gammaherpesvirues encode at least one protein with homology to a host purine metabolic enzyme (FGAM synthase). We are seeking to understand how these viral molecules influence replication in cells and pathogenesis in the animal.