This application proposes to investigate the counter-regulating role of androstenediol (AED) in the glucocorticoid (GC)-mediated immunosuppression induced by stress. Many observations in both humans and animals have demonstrated that stress is immunomodulatory and can alter the pathogenesis of microbial infections to the extent that stress may be adverse to health. Stress disrupts homeostasis, and the body responds through endocrine and nervous systems interactions in an effort to re-establish the health of the host. However, the resulting physiology changes associated with stress, such as the rise in serum glucocorticoids, are implicated in suppression of anti-viral immunity. Therefore, it would be of significant importance to counter-regulate stress-mediated immunosuppression during viral infection to improve immune responses and limit virus-mediated damage. This proposal focuses upon the anti-glucocorticoid influence of a native steroid hormone that has been shown to augment immune function and protect animals against lethal viral infections. Androstenediol (5-androstene-3beta, 17beta-diol, AED), a metabolite of dehydroepiandrosterone (DHEA), confers protection against lethal infections with influenza A and coxsackievirus B4. The protective activity appears to counterbalance the function of the regulatory glucocorticoids. Therefore, the studies in this proposal are designed to determine whether immunoregulation by AED counter-regulates the immunosuppressive action of glucocorticoids. More specifically, by counterbalancing the GC-mediated transcriptional regulation of pro-inflammatory, chemotactic, and CD4+ T cell cytokine genes, the PI hypothesizes that AED will restore inflammatory responses to enhance recruitment and activation of antigen-specific cells necessary to restrict virus replication. By counterbalancing the effects of GC at the cellular and molecular levels, AED might prevent the stress-mediated pathologic perturbation of the communication loop between the central nervous system and the immune system and thus promote homeostatic regulation of the pro-inflammatory and cell-mediated immune responses. The long-term goals should provide insight into the relationships between the nervous, endocrine, and immune systems and how inflammatory immune responses can be regulated at many different central and peripheral levels.