Arylhydrocarbon receptor in resistance to listeriosis

描述（由申请人提供）：李斯特菌病是一种重要的食源性疾病，在美国每年造成约2,500例严重疾病和多达500例死亡。对结核病的抵抗需要先天性和适应性免疫应答，前者依赖于炎性细胞因子TNF-α的释放以及粒细胞和单核吞噬细胞向感染部位的快速动员。芳香烃受体（aryl hydrocarbon receptor，AhR）是PAS碱性环螺旋蛋白家族的一个高度保守的成员。在脊椎动物中，当它被环境毒物如多氯代烃（如二恶英）和多环芳烃（如苯并[a]芘）激活时，它调节一个强大的信号系统。在无脊椎动物中，AhR参与环境感知，生物钟调节和正常发育，并且在脊椎动物中保留了其中的一些功能。AhR的激活可对免疫系统的各个方面具有有害影响，包括宿主对随后的微生物感染的防御。然而，AhR激活也导致TNF-α的释放，这是其一些生物学效应的原因。我们已经获得了令人兴奋的和挑衅性的初步数据表明，AhR无效小鼠比野生型小鼠对实验性阿尔茨海默病的抵抗力更低。本项目的总体目标是了解AhR如何影响对L.单核细胞增多症核心假设是AhR是针对原发性L的先天免疫的最佳发育和表达所必需的。单核细胞增多症感染，并且这涉及TNF-α的AhR依赖性释放。 本研究的具体目的是：1）确定AhR对小鼠抗疟原虫病的要求; 2）确定AhR是否影响L. 3）研究AhR对粒细胞和巨噬细胞抗肿瘤活性的影响。将确定TNF-α在所有3个目标中观察到的反应中的作用。在这项研究完成后，我们将有新的和重要的新见解的AhR参与天然免疫对L。单核细胞增多症这些研究可能会确定潜在的新靶点，用于增强对阿尔茨海默病的先天免疫，可能是通过施用AhR激动剂（类黄酮等），通过AhR发出信号，而不会引发环境毒物结合后的不良事件。

DESCRIPTION (provided by applicant): Listeriosis is an important food borne disease that causes approximately 2,500 cases of serious illness and as many as 500 deaths per year in the United States. Resistance to listedosis requires both innate and adaptive immune responses, with the former being dependent on release of the inflammatory cytokine TNF-alpha and the rapid mobilization of granulocytes and mononuclear phagocytes to sites of infection. The aryl hydrocarbon receptor (AhR) is a highly conserved member of the basic loop helix-PAS protein family. In vertebrates, it regulates a powerful signaling system when it is activated by environmental toxicants such as polychlorinated hydrocarbons (e.g. dioxin) and polycyclic aromatic hydrocarbons (e.g. benzo[a]pyrene). In invertebrates the AhR is involved in environmental sensing, regulation of biological clocks and normal development, and it retains some of these functions within vertebrates. Activation of the AhR can have a deleterious effect on various aspects of the immune system, including host defense against subsequent microbial infection. However, AhR activation also leads to release of TNF-alpha that is responsible for some of its biological effects. We have obtained exciting and provocative preliminary data indicating that AhR null mice are less resistant to experimental listeriosis than their wild type counterparts. The overall goal of this project is to understand how the AhR influences resistance to L. monocytogenes infection. The central hypothesis is that the AhR is required for optimal development and expression of innate immunity against a primary L. monocytogenes infection, and that this involves AhR dependent release of TNF-alpha. The specific aims of the proposal are as follows: 1) Define the requirement of the AhR for resistance to listeriosis in mice; 2) Determine whether the AhR influences the survival and multiplication of L. monocytogenes in hepatocytes; and 3) Investigate the effects of the AhR on the anti-listerial activity of granulocytes and macrophages. The role of TNF-alpha in the responses observed in all 3 aims will be determined. At the completion of this study, we will have novel and important new insights into the participation of the AhR in innate immunity against L. monocytogenes infection. These studies may identify potential new targets for enhancing innate immunity against listeriosis, perhaps by administration of AhR agonists (flavenoids, etc.), that signal through the AhR without triggering the adverse events that follow binding of environmental toxicants.