Viruses are ubiquitous infectious agents whose manifested virulence ranges from subclinical infections to devastating diseases such as AIDS. Given data demonstrating extensive interconnection between the nervous, endocrine, and immune systems, the role of adrenal steroid-immune interaction in modulating immune responses to viruses is a potentially important factor in determining onset, course, and outcome of viral diseases. In the previous project period, the investigators have begun to define the conditions and consequences of adrenal steroid-immune interactions in viral infections. Specifically, the investigators have delineated the capacity of several viruses to interact with the hypothalamic-pituitary-adrenal axis with the resultant release of glucocorticoids. They also have identified an early interleukin (IL)-6 dependent pathway of glucocorticoid induction during infection with murine cytomegalovirus (MCMV) and have documented the capacity of viral infection and cytokines to directly influence glucocorticoid receptors. Finally, they have demonstrated the role of endogenous glucocorticoids in protection against fatal overproduction of tumor necrosis factor-alpha during viral infection. The proposed continuation of this work, which represents the integrated efforts of two laboratories, is designed to further evaluate 1) the mechanisms by which viral infections activate neuroendocrine pathways, 2) how immune signals are translated into neuroendocrine signals, 3) how neuroendocrine signals are received by target immune tissues, and 4) how the neuroendocrine system shapes immune responses to viruses. Specific hypotheses are that a) inflammatory cells trafficking to the liver are critical components of the IL-6 response to MCMV, b) the IL-6 dependent glucocorticoid response to MCMV is mediated through induction of corticotropin releasing factor, c) immunoregulatory cytokines (e.g., interferon-gamma) facilitate while proinflammatory cytokines (e.g., IL-1alpha) inhibit glucocorticoid receptor function, and d) glucocorticoids mediate their effects on immune responses by shaping T cell responses and facilitating the delivery of immune cells to relevant target tissues including the liver. Finally, studies with MCMV and lymphocytic choriomeningitis virus (LCMV) clone E350 will be complemented by characterization of adrenal steroid-immune interactions in mice infected with LCMV clone 13 which induces a late glucocorticoid response coincident with loss of T cell function and viral persistence. Taken together, these studies will provide the foundation for developing new treatment strategies for immunomodulation drawing upon advances in neuroendocrinology and the neurosciences.
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