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系统性疾病 避免被宿主免疫系统清除的炭疽病。炭疽毒素，由保护性抗原组成 (PA)、水肿因子(EF)和致死因子(LF)，作为毒素是导致疾病的主要因素 抑制免疫细胞功能。因此，对炭疽毒素作用机制的洞察提供了 了解炭疽杆菌发病机制所需的关键信息。在当前项目中 本实验旨在阐明水肿型毒素(ET：PA+EF)对天然免疫的影响。 反应，并确定ET如何与致命毒素(LT：PA+LF)结合来完成这一过程。 在PA转位到细胞内后，EF作为腺苷环化酶发挥作用，并产生高水平的 夏令营。在最近的研究中，我们发现ET激活糖原合成酶激酶-3|3(GSK-3)。 3(3)导致β-连环蛋白失活和(3-连环蛋白)共转录调节丧失。这些项目的目标是 现在的研究是阐明ET对免疫细胞功能的影响以及由此产生的影响 对人肺泡巨噬细胞和外周血单核细胞的作用，以及测定 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：我们将表征ET诱导的炎症反应和 细胞内信号在早期阶段引起严重的免疫抑制 吸入性炭疽病 具体目标2：我们将表征ET诱导的炎症反应和细胞内的变化 在吸入性炭疽病后期引起严重免疫抑制的信号 具体目标3：我们将描述ET和LT在免疫抑制中的联合作用 在炭疽病的早期和晚期。

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.