Recent observations in both humans and animal models have demonstrated that stress is immunomodulatory, and can alter the pathogenesis of microbial infections to the extent that stress may be aversive to health. Stress has been shown to increase the susceptibility to, and severity of, the viral infectious disease process. It is most important that the mechanisms underlying enhanced disease susceptibility be fully understood so that the appropriate therapeutic strategies can be applied, or new ones developed. The mammalian response to a stressor is primarily mediated by two neuroendocrine systems: the sympathetic nervous system (SNS) and the hypothalamic-pituitary-adrenal (HPA) axis. This revised proposal focuses on neuroendocrine regulation of immunity during viral infection, particularly as it pertains to lymphocyte localization, activation, and effector function. The overall purpose is to examine the neuroendocrine mechanisms (with emphasis on glucocorticoid and catecholamine responses) that modulate specific anti-viral immune responses and thus alter the pathophysiology of the infectious disease process. We have shown that restraint stress significantly suppresses Th1 responses (IL-2), while anti-viral antibody responses, which require Th2 activation, are essentially intact. Other studies have shown that elevated glucocorticoid (GC) levels suppress IL-2 and enhance IL-4 responses. We previously have shown elevated and sustained levels of GC in infected/stressed mice, and would expect that neuroendocrine responses regulate the balance of Th1/Th2 subset activation. We also have found that restraint stress reduces leukocyte infiltration into sites of infection as well as decreasing the cellularity of the regional lymph nodes draining those sites. Although lymphadenopathy was restored by treating stressed animals with a glucocorticoid receptor antagonist, T cell activation in the draining lymph nodes remained suppressed unless a Q-adrenergic receptor antagonist was given. Therefore, our preliminary data has led us to hypothesize that the reduced inflammatory response in restraint-stressed mice is due either to direct inhibition of cellular adhesion molecule expression by GC or indirectly via down-regulating secretion of pro-inflammatory cytokines and chemokines from resident cells such as macrophages and neutrophils. In addition, antagonism of the (3-adrenergic receptor suggested a role for catecholamine in regulation of T cell activation. Thus, we hypothesize that stress acts as a co- factor in the progression of infection by enhancing Th2 while diminishing the proinflammatory Th1 responses to viral antigen.
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