Epstein-Barr virus (EBV) infects more than 90% of the world's population and is implicated in the pathogenesis of several B-cell and epithelial malignancies, including Burkitt's lymphoma, nasopharyngeal carcinoma and Hodgkin's disease, as well as other non-cancer diseases, such as multiple sclerosis and chronic fatigue syndrome. Physical and psychological stress is known to induce reactivation of latent EBV and we have recently shown that glucocorticoids, which are produced during stress, induce expression of the immediate-early lytic switch gene BZLF1. However, the molecular mechanism behind stress hormone-mediated reactivation of latent EBV is poorly understood. My long-term goal is to identify the molecular processes by which physiological and psychological stress affect latent viruses. Our central hypothesis is that stress induces reactivation of latent EBV through glucocorticoid induction of the immediate-early genes, BZLF1 and/or BRLF1. The rationale that underlies the proposed research area is that understanding how stress affects EBV in latently infected cells will provide useful information for understanding the pathology associated with EBV-related diseases. We plan to test our central hypothesis by pursuing the following specific aims. 1. Induction of the EBV immediate-early lytic switch genes by glucocorticoids. To attain this aim glucocorticoid induction of BZLF1 and BRLF1 mRNA and protein in both B-cell and epithelial cell derived EBV genome positive cell lines will be analyzed. 2. Identification of the region of the Zp and Rp promoter that responds to glucocorticoids. To attain this aim glucocorticoid induction of the Zp and Rp promoters and identification of the responsive regions will be determined. In addition, GR-DNA interactions on these promoters will be determined. The contribution of the proposed research is expected to be in the identification of the molecular mechanism by which stress, through glucocorticoids, induces EBV immediate-early genes, thereby inducing reactivation of latent virus. This contribution is significant because it would identify pharmacological targets to prevent stress-mediated EBV reactivation which would prevent spread of infection and also provide new therapeutic targets for EBV-related diseases.
The proposed research is relevant to public health because it will identify the mechanism by which physical and psychological stress induces reactivation of latent EBV. Currently the effect of stress on EBV-related carcinomas are unknown although there is evidence of the detrimental effect of stress in other EBV-related diseases such as chronic fatigue syndrome. This is relevant to the mission of the NIH as this research will provide the basic information needed for the development of new therapies for EBV-related diseases.
