Human gammaherpesviruses (GHVs) are potent oncoviruses that ubiquitously infect people worldwide. These viruses, Epstein-Barr virus (EBV) and Kaposi sarcomaassociated herpesvirus (KSHV), are strongly associated with numerous human malignancies, development of which is potently influenced by host immunodeficiency. As obligate intracellular pathogens, GHVs must rely on the host as a source of metabolic building blocks for virus components and synthesis machinery. However, millions of years of co-evolution shared by GHVs and host resulted in a complex array of antiviral genes developed by the host, and a series of viral factors that combat and nullify the host anti-viral sentinel effectors. Thus, the ongoing conflict between host immunity and GHVs is elegantly balanced by the interaction of these factors, and rarely results in complete clearance of the virus or disease in the host. The host tumor suppressor protein p53, which is triggered by numerous cellular stresses, is a powerful mediator of cell fate. p53 functions as a transcription factor that transactivates genes to halt cell cycle or facilitate death of its cell experiencing stress. Using the small animal model of GHV pathogenesis, murine gammaherpesvirus-68 (MHV68), we performed studies to identify roles of p53 during each phase of the infectious cycle. Although induced during acute MHV68 infection, p53 was functionally deactivated by the specific viral genes mLANA and muSOX. Thus, cells lytically-infected by MHV68 were protected from p53- mediated agonists. However, we found that p53 plays a critical role in restricting latent colonization of MHV68 during chronic infection, where p53-deficient mice exhibited drastically elevated MHV68 frequencies of infection. p53 also protected mice from lethal malignancy associated with MHV68 infection. Finally, we identified a splenic lymphoid progenitor cell type, lineage-Sca-1+c-Kit- (LSK-) that is an early reservoir for MHV68 latency and develops into B cells that maintain virus latency. These studies reveal the important interactions of p53 with MHV68 during each stage of infection.
|Advisor:||Forrest, James C.|
|Commitee:||Chambers, Timothy, Chow, Marie, Ponnappan, Usha, Stumhofer, Jason, Zhang, Xuming|
|School:||University of Arkansas for Medical Sciences|
|Department:||Microbiology and Immunology|
|School Location:||United States -- Arkansas|
|Source:||DAI-B 77/11(E), Dissertation Abstracts International|
|Keywords:||DNA damage response, Herpesvirus, MHV68, P53, Virus|
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