STRESS MEDIATION OF ENDOCRINE-IMMUNE-INFECTIOUS TRIAD

内分泌-免疫-感染三联征的应激调节

• 批准号: 2249768
• 负责人: MARK LYTE
• 金额: $ 14.15万
• 依托单位: MINNESOTA STATE UNIVERSITY, MANKATO
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-04-01 至 1998-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2249768
• 关键词: Enterobacteriaceae; SDS polyacrylamide gel electrophoresis; bacterial disease; catecholamines; conflict; disease /disorder proneness /risk; enzyme linked immunosorbent assay; genetic strain; host organism interaction; immune system; laboratory mouse; neuroendocrine system; neuroimmunomodulation; polymerase chain reaction; psychological stressor; psychoneuroimmunology; stress; western blottings

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.

压力改变对感染性挑战的易感性的能力是 目前认为是由免疫系统的神经内分泌调节引起的。 响应能力。 本提案中评估的假设是， 神经内分泌系统和非免疫系统之间的相互作用 感染生物体还负责应激诱导的 传染病发病机理的改变。这种假设是 基于我们的发现，在体外， 细菌生长，毒力因子表达增加， 一种假定的非α、非β肾上腺素能受体的部分阐明 对革兰氏阴性菌的作用 第一个具体目标将建立自然主义的能力， 改变易感性的社会冲突的行为学相关应激源 感染性口腔挑战与人类细菌的主要模型， 侵袭性，小肠结肠炎耶尔森氏菌，在耐药C57 BL/6和 易感DBA/2小鼠。根据第二个具体目标， 腔室植入法，有效地隔离细菌， 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 vivo.初步数据表明，Y。 与处理相比， 对照动物。第三个具体目标将利用内分泌操纵 C57 BL/6和DBA/2小鼠，以确定参与应激的途径。 引起感染易感性的改变。 第四个具体目标 将研究社会冲突压力改变生产的能力， 作为抗微生物剂的鼠肠防御素cryptdin-1 参与宿主肠道防御细菌感染的肽。 初步数据表明，社会冲突压力会产生 Cryptdin-1 mRNA产生的显著减少，同时 导致肠组织的细菌定植增加， 口服耶尔森氏菌第五个具体目标审查了 体液和细胞以及特异性白细胞介素对 社会冲突压力下的耶尔森氏菌感染。统称 完成拟议的实验将确定直接原因， 内分泌、免疫、 压力导致的传染性方面。 因此，这些研究将提供深入了解的发病机制， 通过检查感染生物体的能力， 积极响应压力引起的神经内分泌活动的变化。 这种途径与目前的心理神经免疫学 一种将感染易感性的改变视为 仅仅是由于应激诱导的免疫系统改变而发生的。 负责防御感染因子的机制。因此，在本发明中， 这一建议可提供适用于艾滋病研究的信息 由于艾滋病继发感染的进展，以及 原发性HIV病毒本身，可能部分依赖于心理因素， 受害者所经历的压力。