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"Toxoplasma gondii: neuro-intestinal interactions"

“弓形虫：神经-肠道相互作用”

基本信息

批准号：
7232439
负责人：
FERNANDO P MONROY
金额：
$ 17.96万
依托单位：
NORTHERN ARIZONA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-05-15 至 2010-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7232439
关键词：
Acquired Immunodeficiency Syndrome Acute Adrenal Glands Adrenal Medulla Adrenergic Receptor Affect Agonist Animal Model Animals Brain CD4 Positive T Lymphocytes Catecholamines Cell Count Cells Chronic stress Clinical Communicable Diseases Communication Condition Data Dendritic Cells Disease Disease susceptibility Endocrine Epinephrine Excision Exposure to Foundations Glucocorticoids Goals HIV Hand Homeostasis Hormones Immune Immune response Immune system Immunotherapy Infection Inflammatory Response Interferons Intestines Laboratories Measures Mediating Mediator of activation protein Modeling Mus Nerve Nervous system structure Neuraxis Neurohormones Neuropeptides Neurotransmitters Opportunistic Infections Outcome Oxidopamine Parasites Pathogenesis Pathology Pathway interactions Patients Peripheral Pharmaceutical Preparations Phase Physiological Positioning Attribute Predisposition Process Range Receptor Activation Regulation Research Resistance Role Route Solid Source Stress Sympathetic Nervous System Synapses System T-Lymphocyte Toxoplasma Toxoplasma gondii Toxoplasmosis Virulent Water Stress Work cofactor design hypothalamic-pituitary-adrenal axis immune function intraperitoneal nerve supply novel therapeutics pathogen psychopharmacologic response stressor

项目摘要

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.

描述（由申请人提供）：在免疫应答期间，大脑和免疫系统之间存在双向通信以维持体内平衡。两个主要的通路系统参与这种交叉通信，下丘脑-垂体-肾上腺（HPA）轴和交感-肾上腺-髓质（SAM）系统。SAM系统的激活导致从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影响免疫反应并加重HIV疾病。有趣的是，并非所有慢性感染弓形虫的艾滋病患者都会发展为临床疾病，这表明除了低CD 4 T细胞计数外，还有其他因素影响发病机制。我们的长期目标是了解应激激素和神经肽如何调节机会寄生虫弓形虫感染。本申请的目的是研究去甲肾上腺素（N-EPI）的作用，SAM系统的主要介质作为辅因子在肠道病理学的小鼠口服感染应激条件下。本研究的理论基础是易感的C57 BI/6小鼠在经口感染T.弓形虫由于肠道病理驱动的部分干扰素（IFN）-？通过固有层（LP）CD 4 + T细胞释放;而冷水应激（CWS）可能通过减少CD 4 + T细胞驱动的肠道病理学来提高这些小鼠的存活率。我们推测一个潜在的机制可能涉及肾上腺交感神经调节肠道T细胞活性在应激动物，导致改变肠道免疫反应T。弓形虫感染为了实现本申请的目的，我们将采用温和的物理应激（CWS）和T.弓形虫ME 49株。将追求两个具体目标：（1）确定离体N-EPI（交感神经系统（SNS）的主要介质）在CWS期间对LP树突状细胞和CD 4 + T细胞的贡献;和（2）确定N-EPI和外周交感神经支配在CWS和感染期间对LP细胞应答的贡献。在本研究完成后，我们希望能够确定N-EPI在口服T.弓形虫感染除了在理解由中枢神经系统调节的正常生理和宿主防御过程中具有基本应用外，这些结果在设计旨在抑制由增强的炎症反应引起的病理的新的治疗策略中将具有重要价值。