There is substantial evidence from both human and animal studies indicating that the immune system is functionally integrated with both the central nervous system and endocrine system. Recent experimental evidence suggests that the neuroendocrine-immune axis operates bi-directionally in that the immune system receives and responds to signals originating from the nervous and endocrine systems as well as delivering signals to which these systems can each respond. As a result, immune responses are subject to direct neuroendocrine regulation. In addition, a number of studies in both humans and animals have demonstrated that stressful events play a significant role in modulation of both humoral and cellular immunity. However, few studies have focused on elucidating the basic mechanisms that underlie stress-induced modulation of the immune response that is necessary for resolution of a specific virus infection. The overall aim of this proposal is to use an established murine model system of herpes simplex virus (HSV) infection to investigate the mechanisms underlying stress-associated neuroendocrine interactions with the immune system and how these interactions may contribute to the pathogenesis of HSV infection. The focus of this study is necessarily limited to the stress-associated release of corticosterone and epinephrine from the adrenal gland and norepinephrine which is released directly into lymphoid tissues via direct sympathetic neural innervation. The first aspect of these studies examines the effect of these agents on the activation of HSV-specific memory cytotoxic T lymphocytes (CTLm) to the lytic phenotype and the role that an altered lymphokine gene expression in mediating these effects. A complementary approach to investigate these neuroendocrine effects on CTL proliferation and function utilizes an HSV- specific CTL cell line. The second aspect of this proposal extends these in vitro studies to an in vivo model system to determine the effect of restraint stress and the corresponding release of corticosterone, epinephrine and norepinephrine on the ability of HSV-specific CTL to protect against primary and latent HSV infection in vivo. Last, an in vitro approach will be undertaken to study these neuroendocrine effects on HSV antigen processing and presentation that is necessary for HSV-specific CTL activation. The ability to prevent HSV reactivation from the latent state and to limit the severity of recurrent episodes of HSV infection is dependent upon the competence of the immune system of the infected host. However, the underlying basis for such immune modulation culminating in HSV pathogenesis is not understood well. Overall, the studies proposed in this application will provide insight into the role of and mechanisms by which stress-related hormones and neuropeptides modulate anti-viral immune responses and should contribute significantly to the overall understanding of the relationship among stress, immune function, and viral pathogenesis.
