"Innate intestinal responses in murine toxoplasmosis"

“小鼠弓形体病的先天肠道反应”

基本信息

批准号：
6874988
负责人：
FERNANDO P MONROY
金额：
$ 15.14万
依托单位：
NORTHERN ARIZONA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-04-01 至 2007-07-31
项目状态：
已结题

项目摘要

Stress-induced immunomodulation is mediated, in part, through products of the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic nervous system. Stress activates the HPA axis and the sympathetic nervous system leading to the release of glucocorticoids (corticosterone) from the adrenal cortex, and release of catecholamines (epinephrine, nor-epinephrine) from sympathetic nerve terminals and the adrenal medulla. These effects are mediated through interaction with specific receptors known to be present on the surface of immune cells. 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 stress and infection on Toll-like receptor (TLR) reactivity in intestinal epithelial cells (IEC). TLRs are part of the innate immune system of recognition receptors that sense invading pathogens through recognition of pathogen-associated molecular patterns. TLRs differ in their pathogen recognition, but they seem to act through a common signaling pathway leading to activation of nuclear factor kappa B (NF-kappaB) and expression of inflammatory cytokines. The rationale behind this research centers in the fact that susceptible C57BL/6 mice died after peroral T. gondii infection due to intestinal pathology driven by interferon (IFN)-gamma released by CD4+ T cells. We have demonstrated that cold water stress (CWS) or beta-agonists enhance survival of mice orally infected with T. gondii likely by decreasing intestinal pathology. We hypothesize that increased mortality in susceptible C57BL/6 mice after infection is in part due to high expression of TLR by IEC from contact with gut bacteria and their inability to control inflammatory cytokines. The regulated exposure of lEC to specific cytokines during infection may be importantto the generation of functional TLR reactivity. 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 evaluate in vivo the intestinal expression and regulation of TLR2, TLR4, and TLR9 during CWS and T. gondii infection; (2) to determine in vitro, the contribution of TLR agonists and catecholamines in the expression and regulation of TLR2, TLR4, and TLR9 in IEC lines during infection. We expect at the completion of these studies to have demonstrated a cross-talk between the innate and adaptive immune systems during stress and infection in a mucosal environment. In addition to having basic application in understanding normal physiologic and host defensive processes modulated by the CNS, these results will be of great value in designing new therapeutic strategies aimed at curbing pathology induced by enhanced inflammatory responses.

压力诱导的免疫调节部分是通过下丘脑-垂体-肾上腺 (HPA) 轴和自主神经系统的产物介导的。压力会激活 HPA 轴和交感神经系统，导致肾上腺皮质释放糖皮质激素（皮质酮），并从交感神经末梢和肾上腺髓质释放儿茶酚胺（肾上腺素、去甲肾上腺素）。这些作用是通过与已知存在于免疫细胞表面的特定受体相互作用来介导的。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。本应用的目的是研究应激和感染对肠上皮细胞 (IEC) 中 Toll 样受体 (TLR) 反应性的作用。 TLR 是识别受体先天免疫系统的一部分，通过识别病原体相关分子模式来感知入侵的病原体。 TLR 在病原体识别方面有所不同，但它们似乎通过共同的信号通路发挥作用，导致核因子 kappa B (NF-kappaB) 的激活和炎症细胞因子的表达。这项研究背后的基本原理在于，易感 C57BL/6 小鼠在经口弓形虫感染后死亡，原因是 CD4+ T 细胞释放的干扰素 (IFN)-γ 驱动的肠道病理学。我们已经证明，冷水应激（CWS）或β受体激动剂可能通过减少肠道病理来提高口服弓形虫感染小鼠的存活率。我们假设易感 C57BL/6 小鼠感染后死亡率增加的部分原因是 IEC 与肠道细菌接触导致 TLR 高表达以及它们无法控制炎症细胞因子。感染期间 IEC 对特定细胞因子的调节暴露可能对于功能性 TLR 反应性的产生很重要。为了实现本应用的目标，我们将采用温和的物理应激源、CWS 和低毒力弓形虫菌株（ME49 菌株）。我们将追求两个具体目标：（1）在 CWS 和弓形虫感染期间体内评估 TLR2、TLR4 和 TLR9 的肠道表达和调节； (2)体外测定感染期间TLR激动剂和儿茶酚胺对IEC系中TLR2、TLR4和TLR9的表达和调节的贡献。我们期望这些研究完成后能够证明先天性免疫系统和适应性免疫系统在粘膜环境中的应激和感染期间存在相互影响。除了在理解中枢神经系统调节的正常生理和宿主防御过程方面具有基本应用之外，这些结果对于设计旨在抑制由增强的炎症反应引起的病理学的新治疗策略也具有重要价值。