"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。应激激活HPA轴和交感神经系统，导致糖皮质激素（皮质酮）从肾上腺皮质释放，以及儿茶酚胺（肾上腺素、去甲肾上腺素）从交感神经末梢和肾上腺髓质释放。这些作用是通过与已知存在于免疫细胞表面的特异性受体相互作用介导的。我们的长期目标是了解应激激素和神经肽如何调节机会寄生虫弓形虫感染。本申请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是识别受体的先天免疫系统的一部分，其通过识别病原体相关的分子模式来感测入侵病原体。TLR在其病原体识别方面不同，但它们似乎通过共同的信号传导途径起作用，导致核因子κ B（NF-κ B）的活化和炎性细胞因子的表达。这项研究背后的基本原理是，易感的C57 BL/6小鼠在口服T。弓形虫感染是由于肠道病理由干扰素（IFN）-γ释放的CD 4 + T细胞驱动。我们已经证明，冷水应激（CWS）或β-受体激动剂提高口服感染T。可能是通过减少肠道病变。我们假设易感C57 BL/6小鼠感染后死亡率增加部分是由于IEC与肠道细菌接触时TLR的高表达及其无法控制炎性细胞因子。在感染过程中，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。为了实现本申请的目的，我们将采用温和的物理应激物CWS和T.弓形虫ME 49株。本研究有两个目的：（1）研究CWS和T.弓形虫感染;（2）体外研究TLR激动剂和儿茶酚胺在感染过程中对IEC细胞TLR 2、TLR 4和TLR 9表达和调节的作用。我们期望在完成这些研究时，已经证明了在粘膜环境中的应激和感染期间先天性和适应性免疫系统之间的串扰。除了在了解正常的生理和主机的防御过程中调制的中枢神经系统的基本应用，这些结果将是非常有价值的设计新的治疗策略，旨在遏制病理引起的炎症反应增强。

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.