The long term objectives of this competitive renewal of a Research Scientist Development Award (K02 series) are designed to provide the applicant with scientific training in viral immunology using experimental murine infections and to extend knowledge gained from this work to a clinical context. Training in viral immunology will be achieved by conducting a collaborative research project with Dr. Christine Biron, a viral immunologist at Brown University, examining interactions between adrenal steroids (or glucocorticoids) and the immune system during viral infections. Work with Dr. Biron over the previous project period has 1) demonstrated an IL-6-dependent pathway for the induction of endogenous glucocorticoids during infection with murine cytomegalovirus (MCMV), 2) characterized effects of viral infection on the receptors for glucocorticoids and 3) revealed the contribution of endogenous glucocorticoids to protection against lethality in MCMV infection via negative regulation of tumor necrosis factor (TNF)alpha.
Specific aims for the proposed research plan are 1) to further investigate the mechanisms by which viral infections activate neuroendocrine pathways, 2) to determine how immune signals are translated into neuroendocrine signals in the central nervous system, 3) to determine how neuroendocrine signals are received by target immune tissues (e.g., at the level of the glucocorticoid receptor) and 4) to examine the impact of the neuroendocrine system on specific immune responses to the virus including both cellular and cytokine responses. In addition, to develop skills in clinical research, information from the basic science studies will be integrated into an examination of the impact of the type I interferon (IFN), IFNalpha, on neuroendocrine function and behavior in patients undergoing high dose IFNalpha therapy for malignant melanoma. INFalpha is an important early cytokine in viral infections and has been shown to induce glucocorticoids and IL-6 in humans. Moreover, IFNalpha has been associated with glucocorticoid receptor changes in patients with HIV infection. The INFalpha project will also examine whether antidepressants, which the applicant has found facilitate glucocorticoid receptor function, will increase glucocorticoid-mediated negative feedback on proinflammatory cytokines including TNFalpha and thereby reduce the toxicity associated with high dose cytokine (IFNalpha) exposure. Finally, the applicant will serve as a primary mentor in an HIV/AIDS clinical research training program and extend examination of adrenal steroid-immune interactions to patients with HIV infection. Further understanding of neuroendocrine- immune interactions in viral infections will provide the foundation for developing new therapeutic strategies to limit the immunologic and behavioral morbidity of viral diseases.
| Ruzek, M C; Pearce, B D; Miller, A H et al. (1999) Endogenous glucocorticoids protect against cytokine-mediated lethality during viral infection. J Immunol 162:3527-33 |
| Ruzek, M C; Miller, A H; Opal, S M et al. (1997) Characterization of early cytokine responses and an interleukin (IL)-6-dependent pathway of endogenous glucocorticoid induction during murine cytomegalovirus infection. J Exp Med 185:1185-92 |
