Arylhydrocarbon receptor in resistance to listeriosis

描述(申请人提供)：李斯特菌病是一种重要的食源性疾病，在美国每年导致约2500例严重疾病和多达500人死亡。对列斯特菌病的抵抗既需要先天免疫反应，也需要获得性免疫反应，前者依赖于炎性细胞因子TNF-α的释放，以及粒细胞和单核巨噬细胞快速动员到感染部位。芳香烃受体(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，当它被环境毒物激活时，它调节着一个强大的信号系统，如多氯代烃(如二恶英)和多环芳烃(如苯并[a]芘)。在无脊椎动物中，AhR参与环境感知、生物钟调节和正常发育，并在脊椎动物中保留了其中的一些功能。AhR的激活可能会对免疫系统的各个方面产生有害影响，包括宿主对后续微生物感染的防御。然而，AhR的激活也会导致肿瘤坏死因子-α的释放，而肿瘤坏死因子-α是其某些生物学效应的原因。我们已经获得了令人兴奋和挑衅性的初步数据，表明AhR基因缺失的小鼠对实验性李斯特菌病的抵抗力低于它们的野生型小鼠。该项目的总体目标是了解AhR如何影响对单核细胞增多性李斯特菌感染的抵抗力。中心假设是AhR是针对原发单核细胞增多性李斯特菌感染的先天性免疫的最佳发育和表达所必需的，这涉及到AhR依赖的肿瘤坏死因子-α的释放。该提案的具体目的如下：1)确定AhR对小鼠李斯特菌病的抗性要求；2)确定AhR是否影响单核细胞增多性李斯特菌在肝细胞中的存活和增殖；以及3)研究AhR对粒细胞和巨噬细胞抗李斯特菌活性的影响。将确定在所有三个目标中观察到的反应中肿瘤坏死因子-α的作用。随着这项研究的完成，我们将对AhR参与抗单核细胞增多性李斯特菌感染的先天免疫有新的和重要的见解。这些研究可能确定潜在的新靶点来增强对李斯特菌病的天然免疫力，可能是通过给予AhR激动剂(黄酮类等)，这些激动剂通过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.