Edema Toxin Suppression of Immune Responses During Anthrax Disease

炭疽病从最初的感染发展为严重的全身性疾病，这是由于炭疽杆菌能够避免宿主免疫系统的清除。炭疽毒素由保护性抗原(PA)、水肿因子(EF)和致死因子(LF)组成，是导致疾病的主要因素，因为该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为理解炭疽杆菌的发病机制提供了必要的关键信息。本项目旨在阐明水肿型毒素(ET：PA+EF)对先天性免疫反应的影响，并确定ET如何与致死性毒素(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-连环蛋白失活，失去B-连环蛋白共转录调控。这些研究的目的是阐明ET对免疫细胞功能的影响以及这一过程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。本项目的具体目标是：特定目标1：我们将描述在吸入性炭疽病早期阶段ET诱导的炎症反应和细胞内信号的变化，这些变化是导致吸入性炭疽病早期关键免疫抑制的原因。

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.