Pathways of Glucocorticoid Induction In Viral Infection

Emory University, Atlanta GA

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Abstract

DESCRIPTION: (Provided By Applicant) Based on studies using purified cytokines or cytokine inducers, activation of hypothalamic CRH is considered to be a primary mechanism by which cytokines stimulate the }-IPA axis with the resultant release of glucocorticoids (CORT . Few studies have examined the neuroendocrine pathways by which cytokines stimulate CORT induction during viral infection. As a model of viral infection, murine cytomegalovirus (MCMV) will be used to study the levels of the HPA axis at which virus-induced cytokines can be translated into neuroendocrine signals. The MCMV-induced CORT response is dependent on interleukin-6 (IL-6) and is essential for protection against cytokine-mediated lethality during infection. This proposal will examine the three levels of the HPA axis (hypothalamus, anterior pituitary, and adrenal gland) at which IL-6 (and other MCMV-induced cytokines) can act by determining the dependence of the MCM\ -induced CORT response on the release of CRH and ACTH. In addition, a permissive role for CRH and ACTH in the MCMV-induced CORT response will be investigated. Elucidation of these neuroendocrine-immune interactions in viral infection will help identify the consequences of altered HPA axis set points (ie. chronic stress, depression) on the development and regulation of immune-related diseases. Conversely, altered immunological set points (ie. AIDS. autoimmune diseases) may disrupt neuroendocrine regulation and lead to the development of psychiatric/behavioral disorders. Given the availability of pharmacological agents that can regulate neuroendocrine function, a greater understanding of sites for immune-neuroendocrine interaction will reveal potential therapeutic targets to limit both immunological and behavioral morbidity of viral diseases.