STRESS MEDIATION OF ENDOCRINE-IMMUNE-INFECTIOUS TRIAD

压力改变对感染性挑战的敏感性的能力是 目前认为是免疫的神经内分泌调节所致 响应性。这项提议评估的假设是，直接的， 非免疫性，神经内分泌系统和细胞因子之间的相互作用 感染生物体是压力诱导的另一个原因 传染病发病机制的变化。这一假设是 基于我们的发现，儿茶酚胺在体外特异性地增强了 细菌生长，毒力因子表达增加，以及 一种可能的非α、非β肾上腺素能受体的部分阐明 关于革兰氏阴性细菌。 第一个具体目标是建立自然主义者的能力， 与行为相关的社会冲突应激源改变易感性 以人类细菌体为主要模型的口腔感染性挑战 小肠结肠炎耶尔森氏菌在耐药C57BL/6和 易感DBA/2小鼠。根据第二个具体目的，使用 一种有效分离细菌的室内植入法 与免疫系统的相互作用将提供证据支持 假设直接神经内分泌-细菌相互作用可以发生在 活着。初步数据显示，Y的增长有所增加。 应激组与处理组种植室内小肠结肠炎的比较 控制动物。第三个具体目标将利用内分泌操纵 以确定C57BL/6和DBA/2小鼠参与应激反应的途径。 引起感染易感性的改变。第四个具体目标 将考察社会冲突压力改变生产的能力 作为抗菌剂的小鼠肠道防御素Cryptdin-1 参与宿主肠道防御细菌感染的多肽。 初步数据表明，社会冲突压力会产生 Cryptdin-1mRNA的产量大幅下降，同时 导致肠道组织细菌定植增加 口服耶尔森氏菌。第五个具体目标审查以下几个方面 体液和细胞，以及特异性白细胞介素2的反应 耶尔森氏菌感染期间的社会冲突压力。总体而言， 拟议实验的完成将确定直接原因和 内分泌学、免疫学与骨质疏松症的作用关系 作为压力的结果而具有传染性的方面。 因此，这些研究将为深入了解糖尿病的发病机制提供依据。 通过检查感染的有机体的能力来感染疾病 积极应对压力引起的神经内分泌活动变化。 这条路线与目前的心理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 负责防御传染病病原体的机制。因此， 这一建议可能会为艾滋病的研究提供适用的信息 由于艾滋病继发感染的进展，以及 原发HIV病毒本身，可能部分依赖于心理 受害者所经历的压力。

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.