Edema Toxin Suppression of Immune Responses During 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 炭疽病，以避免由宿主免疫系统清除。炭疽毒素，由保护性抗原组成 (PA)水肿因子（EF）和致死因子（LF）是引起疾病的主要因素， 抑制免疫细胞功能因此，深入了解炭疽毒素的作用机制， 了解B的发病机理所必需的关键信息。炭疽病当前项目中 本实验旨在阐明水肿毒素（ET：PA + EF）对先天性免疫功能的影响， 反应，并确定ET如何与致命毒素（LT：PA加LF）结合来完成这一过程。 在通过PA易位进入细胞后，EF作为腺苷酸环化酶发挥功能，并产生高水平的腺苷酸环化酶。 营近年来的研究发现，ET激活糖原合成酶激酶-3| 3（GSK- 3（3）导致β-连环蛋白失活和β-连环蛋白共转录调节的丧失。这些目标 目前的研究正在阐明ET介导的免疫细胞功能破坏的影响以及这种影响的作用。 人肺泡巨噬细胞和外周血单核细胞的过程，以及确定 ET和LT对这些细胞的联合作用。该项目的具体目标是： 具体目标1：我们将描述ET诱导的炎症反应变化， 细胞内信号传导，其解释了在早期阶段的关键免疫抑制， 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 在吸入性炭疽后期阶段， 具体目标3：我们将描述ET和LT对免疫抑制的联合作用 在炭疽病的早期和晚期阶段。

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.