Immuno-regulation of GI nematode infection

全世界估计有20亿人感染了土壤传播的蠕虫寄生虫，估计有3亿人患有严重感染。该提案的长期目标是更好地了解胃肠道（GI）线虫感染后的免疫调节机制，该机制控制启动，调节和效应反应。鼠鞭虫是小鼠的天然胃肠道线虫，并提供了一种免疫学明确的人类感染模型。以前的研究表明，辅助性T细胞1型（Thl）反应促进慢性感染，而Th 2反应是宿主保护性免疫所必需的。然而，控制T.小鼠的先天免疫系统的识别和Th 2细胞因子如何介导的驱逐， 感染情况不明。初步研究发现NF-κ B1活化在T.泥浆假设NF-κ B1调节抵抗感染所需的三种新途径： (i)肠上皮细胞（IEC）活化;（ii）树突状细胞（DC）反应;和（iii）排出胃肠道线虫所需的新型免疫效应分子-EMAMb的表达。的要求 这些通路在T.将测试泥浆感染。首先，研究了IEC和DC在T.将使用IEC功能特异性受损的遗传操作的动物宿主或纯化的DC群的过继转移来测试小鼠和促炎细胞因子的产生。初步研究还鉴定了一种新的NF-κ B1依赖性免疫效应分子，p53 Mb，介导胃肠道线虫感染的排出。将定义调节BMPb表达的因素和蠕虫被驱逐的机制。定义这些途径将提供 对胃肠道中先天性和适应性Th 2应答的调节有了新的认识，并提供了操纵抗线虫应答的新靶点。

An estimated 2 billion people world-wide are infected with soil transmitted helminth parasites, with an estimated 300 million people suffering severe infections. The long term goals of this proposal are to gain a better understanding of the immuno-regulatory mechanisms that govern the initiation, regulation, and effector responses following gastrointestinal (GI) nematode infection. Trichuris muris is a natural GI nematode of mice and provides an immunologically well-defined model of human infection. Previous studies have shown that T helper type 1 (Thl) responses promote chronic infection, while Th2 responses are required for host protective immunity. However, the cellular and molecular mechanisms that control how T. muris is recognized by the innate immune system and how Th2 cytokines mediate expulsion of infection are unknown. Preliminary studies identified a critical role for NF-kappaB1 activation in immunity to T. muds. It is hypothesized that NF-kappaB1 regulates three novel pathways required for resistance to infection: (i) intestinal epithelial cells (IEC) activation; (ii) dendritic cell (DC) responses; and (iii) expression of RELMb, a novel immune effector molecule required for expulsion of GI nematodes. The requirements for these pathways in immunity to T. muds infection will be tested. First, the role of IEC and DC in innate recognition of T. muris and production of proinflammatory cytokines will be tested using either genetically manipulated animal hosts in which IEC function is specifically impaired, or the adoptive transfer of purified DC populations. Preliminary studies also identified a novel NF-kappaBl-dependent immune effector molecule, RELMb, that mediates expulsion of GI nematode infection. The factors that regulate expression of RELMb and mechanisms through which worms are expelled will be defined. Defining these pathways will provide new insights into the regulation of innate and adaptive Th2 responses in the GI tract and offer novel targets to manipulate anti-nematode responses.