"Innate intestinal responses in murine toxoplasmosis"

应激诱导的免疫调节部分通过下丘脑-垂体-肾上腺（HPA）轴和自主神经系统的产物介导。压力激活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），交感神经末梢和肾上腺髓质释放儿茶酚胺（肾上腺素，去肾上腺素）。这些作用是通过与已知存在于免疫细胞表面的特定受体的相互作用介导的。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。本研究旨在探讨应激和感染对肠上皮细胞（IEC） toll样受体（TLR）反应性的影响。tlr是先天免疫系统识别受体的一部分，通过识别病原体相关的分子模式来感知入侵的病原体。tlr对病原体的识别不同，但它们似乎通过共同的信号通路起作用，导致核因子κ B （nf - κ B）的激活和炎症因子的表达。这项研究的基本原理是，易感的C57BL/6小鼠在经口弓形虫感染后，由于CD4+ T细胞释放的干扰素(IFN)- γ驱动肠道病理而死亡。我们已经证明，冷水应激（CWS）或β激动剂可能通过减少肠道病理来提高口服感染弓形虫的小鼠的存活率。我们假设感染后易感C57BL/6小鼠死亡率增加的部分原因是与肠道细菌接触的IEC高表达TLR以及它们无法控制炎症细胞因子。在感染期间，lEC对特定细胞因子的调节暴露可能对功能性TLR反应性的产生很重要。为了实现这一应用的目标，我们将采用轻度物理应激源CWS和低毒力的弓形虫菌株（ME49菌株）。本研究有两个具体目的：(1)评估CWS和弓形虫感染期间TLR2、TLR4和TLR9在体内的表达和调控；(2)在体外确定TLR激动剂和儿茶酚胺在感染过程中对IEC细胞系TLR2、TLR4和TLR9的表达和调控的贡献。我们期望在完成这些研究时，能够证明在应激和感染的粘膜环境中，先天免疫系统和适应性免疫系统之间存在串扰。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，这些结果将在设计旨在抑制炎症反应增强引起的病理的新治疗策略方面具有重要价值。

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.