Immuno-regulation of GI nematode infection

胃肠道线虫感染的免疫调节

• 批准号: 7388169
• 负责人: David Artis
• 金额: $ 36.86万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7388169
• 关键词: Address; Adoptive Transfer; Animals; Biological Models; Cell Differentiation process; Cell physiology; Chronic; Defect; Dendritic Cells; Development; Epithelial Cells; Exposure to; Gastrointestinal tract structure; Germ-Free; Goals; Goblet Cells; Helminths; Human; Immune; Immune response; Immune system; Immunity; In Vitro; Infection; Interferons; Interleukin-12; Interleukin-13; Interleukin-18; Interleukin-4; Interleukin-6; Intervention; Intestines; Mediating; Modeling; Molecular; Mus; Natural Immunity; Nematoda; Nematode infections; Parasites; Pathway interactions; Population; Production; Proteins; Regulation; Research Personnel; Resistance to infection; Role; Signal Transduction; Soil; System; T-Cell Activation; T-Cell Receptor; Testing; Th2 Cells; Transgenic Organisms; Trichuris; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; base; cell type; cytokine; design; gastrointestinal; human TNF protein; in vivo; insight; novel; pathogen; response; tool

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.

据估计，全世界有20亿人感染了土壤传播的蠕虫寄生虫，其中估计有3亿人遭受严重感染。这项建议的长期目标是更好地了解免疫调节机制，这些机制控制着胃肠道线虫感染后的启动、调节和效应反应。毛滴虫是一种天然的小鼠胃肠道线虫，为人类感染提供了一种免疫学上明确的模型。以前的研究表明，T辅助1型(THL)应答促进慢性感染，而Th2应答是宿主保护性免疫所必需的。然而，控制T细胞如何被先天性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细胞的排出 感染是未知的。初步研究表明，核因子-kappaB1的激活在弓形虫免疫中起着关键作用。据推测，核因子-kappaB1调节三个新的抗感染途径： (I)肠上皮细胞(IEC)的激活；(Ii)树突状细胞(DC)的反应；以及(Iii)RELMb的表达，RELMb是一种新的免疫效应分子，需要驱逐GI线虫。对以下各项的要求 我们将测试这些途径对毛滴虫感染的免疫力。首先，IEC和DC在T.Muris的先天识别和促炎细胞因子产生中的作用将通过使用IEC功能特别受损的基因操纵的动物宿主或通过过继转移纯化的DC群体来测试。初步研究还发现了一种新的依赖于NF-kappaB1的免疫效应分子RELMb，它介导了胃肠道线虫感染的排泄。调节RELMb表达的因素和驱除蠕虫的机制将被定义。定义这些途径将提供 对胃肠道固有和适应性Th2反应的调节有了新的见解，并为操纵抗线虫反应提供了新的靶点。