"Toxoplasma gondii: neuro-intestinal interactions"

描述(申请人提供)：在免疫反应期间，大脑和免疫系统之间存在双向通信，以维持体内平衡。这种交叉联系涉及两个主要的通路系统，即下丘脑-垂体-肾上腺(HPA)轴和交感-肾上腺-延髓(SAM)系统。激活SAM系统导致交感神经末梢和肾上腺髓质释放儿茶酚胺。糖皮质激素和儿茶酚胺都会影响免疫反应，并加剧艾滋病毒疾病。有趣的是，并不是所有慢性感染弓形虫的艾滋病患者都会出现临床疾病，这表明除了低CD4T细胞计数外，还有其他因素影响发病。我们的长期目标是了解应激激素和神经肽如何调节机会性寄生虫弓形虫的感染。本研究旨在探讨SAM系统的主要介导物去甲肾上腺素(N-EPI)在应激条件下口服感染小鼠肠道病理中的辅助作用。这项研究背后的理论基础集中在以下事实：易感的C57BI/6小鼠在口服感染弓形虫后死亡，部分原因是由干扰素(干扰素)驱动的肠道病理。由板层(LP)CD4+T细胞释放；而冷水应激(CWS)可能通过减少CD4+T细胞驱动的肠道病理来提高这些小鼠的存活率。我们假设，一个潜在的机制可能涉及肾上腺交感神经调节应激动物的肠道T细胞活动，导致肠道对弓形虫感染的免疫反应改变。为了实现这一应用的目标，我们将使用温和的物理应激源(CWS)和低毒力的弓形虫株(ME49株)。我们将追求两个特定的目标：(1)在体外确定交感神经系统(SNS)的主要介质N-EPI在慢性疲劳综合征(CWS)中对LP树突状细胞和CD4+T细胞的贡献；(2)确定在CWS和感染过程中N-EPI和外周交感神经支配对LP细胞反应的贡献。在这项研究完成时，我们希望确定N-EPI在经口感染弓形虫期间应激诱导的肠道细胞反应变化中的作用。除了在了解中枢神经系统调节的正常生理和宿主防御过程方面有基础应用外，这些结果还将对设计新的治疗策略以遏制由增强的炎症反应引起的病理变化具有重要价值。

DESCRIPTION (provided by applicant): During an immune response bi-directional communication exists between the brain and the immune system to maintain homeostasis. Two major pathway systems are involved in this cross-communication, the hypothalamic-pituitary-adrenal (HPA) axis and the sympatho-adrenal-medullary (SAM) system. Activation of the SAM system leads to release of catecholamines from sympathetic nerve terminals and from the adrenal medulla. Both glucocorticoids and catecholamines affect immune responses and exacerbate HIV disease. Interestingly, not all AIDS patients chronically infected with Toxoplasma develop clinical disease suggesting factors in addition to low CD4 T cell counts influence pathogenesis. Our long-range goal is to understand how stress hormones and neuropeptides regulate infection by the opportunistic parasite Toxoplasma gondii. The objective of this application is to investigate the role of the nor-epinephrine (N-EPI), the main mediator of the SAM system as cofactor in the intestinal pathology of mice orally infected under conditions of stress. The rationale behind this research centers in the fact that susceptible C57BI/6 mice died after peroral infection with T. gondii due to intestinal pathology driven in part by interferon (IFN)-? released by lamina propia (LP) CD4+ T cells; while cold water stress (CWS) enhanced the survival of these mice likely by decreasing CD4+ T cell-driven intestinal pathology. We hypothesize that a potential mechanism may involve adreno-sympathetic regulation of intestinal T cells activity in stressed animals, leading to altered intestinal immune responses to T. gondii infection. To accomplish the objectives of this application, we will employ a mild physical stressor (CWS) and a low virulent strain of T. gondii (ME49 strain). Two specific aims will be pursued: (1) to determine ex vivo the contribution of N-EPI, the main mediators of the sympathetic nervous system (SNS) on LP dendritic cells and CD4+ T cells during CWS; and (2) to determine the contribution of N-EPI and peripheral sympathetic innervations on LP cellular responses during CWS and infection. At the completion of this research, we expect to have determined the contributions of N-EPI to the stress-induced changes in intestinal cellular responses during peroral T. gondii infection. In addition to having basic application in understanding normal physiologic and host defensive processes modulated by the central nervous system, these results will be of great value in designing new therapeutic strategies aimed at curbing pathology induced by enhanced inflammatory responses.