Edema Toxin Suppression of Immune Responses During Anthrax Disease

由于炭疽芽孢杆菌能够避免宿主免疫系统的清除，炭疽病从最初的感染发展为严重的全身性疾病。炭疽毒素由保护性抗原（PA）、水肿因子（EF）和致死因子（LF）组成，是抑制免疫细胞功能的主要致病因素。因此，深入了解炭疽毒素的作用机制为了解炭疽杆菌的发病机制提供了必要的关键信息。本项目实验旨在阐明水肿毒素（ET: PA + EF）对先天免疫反应的影响，并确定ET如何与致死毒素（LT: PA + LF）联合完成这一过程。经PA转运进入细胞后，EF作为腺苷酸环化酶发挥作用并产生高水平的cAMP。在最近的研究中，我们发现ET激活糖原合成酶激酶3B (GSK- 3B)，导致B-catenin失活和B-catenin协同转录调控缺失。目前这些研究的目的是阐明ET介导的破坏免疫细胞功能的影响及其对人肺泡巨噬细胞和外周血单核细胞的影响，并确定ET和LT对这些细胞的联合作用。该项目的具体目标是：特异性目标1：我们将描述et诱导的炎症反应和细胞内信号的变化，这些变化是吸入性炭疽早期关键免疫抑制的原因特异性目标2：我们将描述et诱导的炎症反应和细胞内信号的变化，这些变化是吸入性炭疽晚期关键免疫抑制的原因特异性目标3：我们将描述ET和LT对炭疽病早期和晚期免疫抑制的联合作用。

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-3B (GSK- 3B leading to inactivation B-catenin and loss in B-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.