STRESS/BACTERIAL INTERACTIONS IN INFECTIOUS DISEASE

描述(申请人的摘要)：压力改变的能力 对传染性挑战的易感性目前被认为是由 免疫反应的神经内分泌调节。假说 在此应用程序中评估的是直接的、非免疫的、相互作用 在神经内分泌系统和感染机体之间有 此外，还对应激诱导的发病机制的改变负责 传染病的风险。这一假设是基于研究人员的 儿茶酚胺对体内外特异性增强作用的研究 细菌生长和毒力因子表达增加。 第一个具体目标是建立自然主义者的能力， 与病因相关的社会冲突应激源改变易感性 以小鼠为感染性口腔炎动物模型的初步研究 细菌侵袭性，小肠结肠炎耶尔森氏菌。第二个具体目标 将研究儿茶酚胺的体外分子机制 影响耶尔西氏菌生长和产生暴力的因素。 这些实验包括对去甲肾上腺素诱导的 细菌生理学和分子指纹的变化，将 提供必要的机械信息的重要部分，以 对随后的活体实验结果进行剖析。根据第三条 具体目的：使用闭合和开放腔内植入方法将 提供活体环境，以确定应激诱导的变化 细菌的发病机制是由直接的神经内分泌细菌引起的 相互作用(密闭室)。初步数据显示， 小肠结肠炎耶尔森氏菌在应激条件下密闭植入腔内的生长 与被处理的对照动物相比，从而支持了这样的假设 在体内可以发生直接的神经内分泌-细菌相互作用。第四次 特定目的将利用内分泌操纵的小鼠来确定 参与应激诱导的感染性脑血管病变的通路 敏感度。第五个具体目标将检查结果是否 用革兰氏阴性菌小肠结肠炎耶尔森氏菌获得的 一种革兰氏阳性细菌。这些体外实验将确定 神经内分泌-细菌直接相互作用的理论适用于 其他感染源。总体而言，完成拟议的 实验将建立一种直接的因果关系 作为压力的结果的内分泌和感染性方面。这个 RSDA将提供必要的时间来发展技术专长和 促进严格测试所需的协作努力 传染病中的应激-细菌相互作用理论。这些 因此，研究将为了解传染性疾病的发病机制提供洞察力。 通过检查受感染的有机体主动 对压力引起的神经内分泌活动的改变做出反应。这 路线与目前的精神神经免疫学有很大不同 将感染易感性的变化视为 仅仅是由于应激引起的免疫系统改变的结果 负责防御感染的机制。

DESCRIPTION (Applicant's abstract): 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.