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 application 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 the investigators' findings of catecholamine specific enhancement of in vitro and in vivo bacterial growth and increased expression of virulence factors. The first Specific Aim will establish the ability of the naturalistic, etiologically relevant stressor of social conflict to alter susceptibility in mice to infectious oral challenge with the primary model of human bacterial invasiveness, Yersinia enterocolitica. The second Specific Aim will examine the in vitro molecular mechanisms by which catecholamines influence the growth of Yersinia and the production of violence factors. These experiments, which include examination of norepinephrine-induced alterations in bacterial physiology and molecular fingerprinting, will provide a significant part of the mechanistic information necessary to dissect results from subsequent in vivo experiments. According to the third Specific Aim the use of both closed and open chamber implant methods will provide in vivo environments to identify whether stress-induced changes in bacterial pathogenesis are due to direct neuroendocrine-bacterial interactions (closed chamber). Preliminary data have demonstrated increased growth of Y. enterocolitica in closed implant chambers of stressed as compared to handled control animal thus supporting the hypothesis that direct neuroendocrine-bacterial interactions can occur in vivo. The fourth Specific Aim will utilize endocrine manipulated mice to determine the pathways participating in stress-induced alterations in infectious susceptibility. The fifth Specific Aim will examine whether the results obtained with the gram-negative bacterium Y. Enterocolitica are applicable to a gram-positive bacterium. These in vitro experiments will determine if the theory of direct neuroendocrine-bacterial interactions is applicable to other infectious agents. Collectively, the completion of the proposed experiments will establish a direct cause and effect relationship between the endocrinological and infectious aspects as a consequence of stress. The RSDA will provide the time necessary to develop the technical expertise and foster the collaborative efforts that are required for the rigorous testing of the theory of stress-bacterial interactions in infectious disease. 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 infection.
