Edema Toxin Suppression of Immune Responses During Anthrax Disease

炭疽病期间水肿毒素抑制免疫反应

• 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
• 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

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，炭疽病疾病从初始感染到严重的全身性疾病 炭疽病避免宿主免疫系统清除。由保护性抗原组成的炭疽毒素 （PA），水肿因子（EF）和致命因子（LF）是毒素作为疾病的主要因素 抑制免疫细胞功能。因此，对炭疽毒素作用机理的见解提供了 了解炭疽芽孢杆菌的发病机理所必需的关键信息。在当前项目中 实验旨在阐明水肿毒素（ET：PA PLUS EF）对先天免疫的影响 响应，并确定ET与致命毒素（LT：PA Plus LF）结合以完成此过程。 通过PA迁移到细胞后，EF充当腺苷酸环化酶并产生高水平 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和（3-catenin共转录调节。 现在的研究旨在阐明ET介导的破坏免疫细胞功能及其影响 在人肺泡巨噬细胞和外周血单核细胞上的过程，并确定 ET和LT对这些细胞的结合作用。该项目的具体目的是： 特定目的1：我们将表征ET引起的炎症反应变化和 细胞内信号传导，解释了早期的关键免疫抑制 吸入炭疽 特定目的2：我们将表征ET诱导的炎症反应变化和插入式的变化 信号在吸入炭疽阶段的后期临界症状。 特定目标3：我们将表征ET和LT对免疫抑制的综合作用 在炭疽病的早期和晚期期间。