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，在美国每年导致大约2500例严重疾病和多达500例死亡。对李斯特菌病的抵抗需要先天免疫和适应性免疫反应，前者依赖于炎症细胞因子tnf - α的释放和粒细胞和单核吞噬细胞对感染部位的快速动员。芳烃受体（AhR）是碱性环螺旋- pas蛋白家族中高度保守的成员。在脊椎动物中，当它被多氯烃（如二恶英）和多环芳烃（如苯并[a]芘）等环境毒物激活时，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一些这些功能。AhR的激活可以对免疫系统的各个方面产生有害影响，包括宿主防御随后的微生物感染。然而，AhR的激活也会导致tnf - α的释放，这是它的一些生物学效应的原因。我们已经获得了令人兴奋和令人振奋的初步数据，表明AhR缺失的小鼠对实验李斯特菌病的抗性比野生型小鼠低。该项目的总体目标是了解AhR如何影响对单核增生乳杆菌感染的抗性。核心假设是，AhR是针对原发性单核细胞增生乳杆菌感染的先天免疫的最佳发育和表达所必需的，这涉及AhR依赖的tnf - α释放。本提案的具体目的如下：1)明确AhR对小鼠李斯特菌病抗性的要求；2)确定AhR是否影响单核增生乳杆菌在肝细胞中的存活和增殖；3)研究AhR对粒细胞和巨噬细胞抗李斯特菌活性的影响。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，我们将对AhR参与抗单核增生乳杆菌感染的先天免疫有新的和重要的新见解。这些研究可能会确定潜在的新靶点，以增强对李斯特菌病的先天免疫，可能是通过给药AhR激动剂（类黄酮等），通过AhR发出信号，而不会引发与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.