The ability of stress to alter susceptibility to infectious challenge is currently believed to result from neuroendocrine modulation of immune responsiveness. The hypothesis evaluated in this proposal is that direct, nonimmune, interactions between the neuroendocrine system and the infecting organism are additionally responsible for stress-induced alterations in the pathogenesis of infectious disease. This hypothesis is based on our findings of catecholamine specific enhancement of in vitro bacterial growth, increased expression of virulence factors and the partial elucidation of a putative non-alpha, non-beta adrenergic receptor on gram-negative bacteria. The first Specific Aim will establish the ability of the naturalistic, ethologically relevant stressor of social conflict to alter susceptibility to infectious oral challenge with the primary model of human bacterial invasiveness, Yersinia enterocolitica, in resistant C57BL/6 and susceptible DBA/2 mice. According to the second Specific Aim the use of a chamber implant method which effectively isolates the bacteria from interaction with the immune system will provide evidence in support of the hypothesis that direct neuroendocrine-bacterial interactions can occur in vivo. Preliminary data has demonstrated increased growth of Y. enterocolitica in implant chambers of stressed as compared to handled control animals. The third Specific Aim will utilize endocrine manipulated C57BL/6 and DBA/2 mice to determine the pathways participating in stress- induced alterations in infectious susceptibility. The fourth Specific Aim will examine the ability of social conflict stress to alter the production of the murine enteric defensin cryptdin-1 which serves as a antimicrobial peptide involved in host intestinal defense against bacterial infection. Preliminary data has demonstrated that social conflict stress produces a profound decrease in cryptdin-1 mRNA production while at the same time resulting in increased bacterial colonization of intestinal tissue by orally administered Yersinia. The fifth Specific Aim examines aspects of the humoral and cellular, as well as specific interleukin, response to Yersinia infection during social conflict stress. Collectively, the completion of the proposed experiments will establish a direct cause and effect relationship between the endocrinological, immunological and infectious aspects as a consequence of stress. These studies will thus provide insight into the pathogenesis of infectious disease by examining the ability of the infecting organism to actively respond to stress-induced alterations in neuroendocrine activity. This route significantly differs from the current psychoneuroimmunological approach in which alterations in infectious susceptibility are viewed to occur solely as a consequence of stress-induced alterations in the immune mechanisms responsible for defense against the infectious agent. As such, this proposal may provide information applicable to the study of AIDS since the progression of the secondary infections in AIDS, as well as the primary HIV virus itself, may be dependent in part on the psychological stress that is experienced by its victims.
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