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3亿人受到严重感染。本研究的长期目标是更好地了解胃肠道（GI）线虫感染后免疫调节机制的启动、调节和效应反应。鼠毛线虫是一种天然的小鼠胃肠道线虫，提供了一种免疫定义明确的人类感染模型。先前的研究表明，辅助性T型1 （Thl）反应促进慢性感染，而Th2反应是宿主保护性免疫所必需的。然而，控制T.鼠如何被先天免疫系统识别的细胞和分子机制，以及Th2细胞因子如何介导T.鼠的排出

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.