Edema Toxin Suppression of Immune Responses During Anthrax Disease

炭疽病期间水肿毒素抑制免疫反应

基本信息

批准号：
7695606
负责人：
Jimmy D. Ballard
金额：
$ 34.41万
依托单位：
OKLAHOMA MEDICAL RESEARCH FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7695606
关键词：
Accounting Adenylate Cyclase Alveolar Macrophages Anthrax Toxin Pathway Anthrax disease Anti-Inflammatory Agents Anti-inflammatory Antigens Attenuated Bacillus anthracis Bacterial Toxins Cell physiology Cells Cyclic AMP Cytokine Activation Cytosol Data Disease Edema Glycogen Synthase Kinase 3 Glycogen Synthase Kinases Goals Health Human Immune Immune response Immune system Immunologics Immunosuppression Infection Inflammatory Inflammatory Response Intoxication Laboratories MAPK14 gene MAPK8 gene Mediating Molecular Pathogenesis Peripheral Blood Mononuclear Cell Phagocytosis Population Process Production Publishing Regulation Signal Pathway Signal Transduction Staging Testing Therapeutic Toxin Virulence Whole Blood Work anthrax lethal factor anthrax toxin base cytokine cytotoxic design edema factor human disease insight interest mortality neutrophil prevent research study

项目摘要

Anthrax disease progresses from initial infection to serious systemic illness due to the ability of Bacillus anthracis to avoid clearance by the host immune system. Anthrax toxin, composed of protective antigen (PA), edema factor (EF), and lethal factor (LF), is a major contributing factor to disease as the toxin suppresses immune cell function. Thus, insights into the mechanism of action for anthrax toxin provides critical information necessary for understanding the pathogenesis of B. anthracis. In the current project experiments are designed to elucidate the effects of edema toxin (ET: PA plus EF) on innate immune responses, and determine how ET combines with lethal toxin (LT: PA plus LF) to accomplish this process. After translocation into the cell by PA, EF functions as an adenylate cyclase and generates high levels of cAMP. In recent studies we have discovered that ET activates glycogen synthase kinase-3|3 (GSK- 3(3) leading to inactivation p-catenin and loss in (3-catenin cotranscriptional regulation. The goal of these studies are now to elucidate the impact ET-mediated disruption immune cell function and the effects of this process on human alveolar macrophages and peripheral blood mononuclear cells, as well as determine the combined effects of ET and LT on these cells. The specific aims of this project are: Specific Aim 1: We will characterize the ET-induced changes in inflammatory responses and intracellular signaling that account for critical immunosuppression during early stages of inhalational anthrax Specific Aim 2: We will characterize the ET-induced changes in inflammatory responses and intracel signaling that account for critical immunosuppression during late stages of inhalational anthrax Specific Aim 3: We will characterize the combined effects of ET and LT on immunosuppression during both early and late stages of anthrax disease.

由于芽孢杆菌的能力，炭疽病从最初的感染发展为严重的全身性疾病炭疽菌以避免被宿主免疫系统清除。炭疽毒素，由保护性抗原组成 (PA)、水肿因子 (EF) 和致死因子 (LF) 是导致疾病的主要因素，因为毒素抑制免疫细胞功能。因此，对炭疽毒素作用机制的深入了解提供了了解炭疽芽孢杆菌发病机制所必需的关键信息。在当前项目中实验旨在阐明水肿毒素（ET：PA 加 EF）对先天免疫的影响响应，并确定 ET 如何与致命毒素（LT：PA 加 LF）结合来完成此过程。通过 PA 易位到细胞中后，EF 作为腺苷酸环化酶发挥作用，并产生高水平的营。在最近的研究中，我们发现 ET 激活糖原合酶激酶-3|3 (GSK- 3(3) 导致 p-catenin 失活和 (3-catenin 共转录调控) 丧失。这些的目标现在的研究正在阐明 ET 介导的免疫细胞功能破坏的影响以及这种影响对人肺泡巨噬细胞和外周血单核细胞的处理，以及确定 ET 和 LT 对这些细胞的综合作用。该项目的具体目标是：具体目标 1：我们将描述 ET 引起的炎症反应变化和细胞内信号传导在早期阶段导致关键的免疫抑制吸入性炭疽具体目标 2：我们将描述 ET 诱导的炎症反应和细胞内变化的特征导致吸入性炭疽晚期关键免疫抑制的信号传导具体目标 3：我们将描述 ET 和 LT 对免疫抑制的综合影响在炭疽病的早期和晚期阶段。