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被宿主免疫系统清除。炭疽毒素由保护性抗原（PA）、水肿因子（EF）和致死因子（LF）组成，是疾病的主要促成因素，因为毒素抑制免疫细胞功能。因此，深入了解炭疽毒素的作用机制为理解B的发病机制提供了必要的关键信息。炭疽病本研究旨在阐明水肿毒素（ET：PA + EF）对天然免疫应答的影响，并确定ET如何与致死毒素（LT：PA + 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cAMP。最近的研究发现，ET激活糖原合成酶激酶-3B（GSK- 3B），导致B-连环蛋白失活和B-连环蛋白共转录调控的丧失。这些研究的目的是阐明ET介导的免疫细胞功能破坏的影响和这一过程对人肺泡巨噬细胞和外周血单核细胞的影响，以及确定ET和LT对这些细胞的联合作用。本项目的具体目标是：具体目标1：我们将描述ET诱导的炎症反应和细胞内信号传导的变化，这些变化是吸入性炭疽早期阶段关键免疫抑制的原因具体目标2：我们将描述ET诱导的炎症反应和细胞内信号传导的变化，这些变化是吸入性炭疽晚期阶段关键免疫抑制的原因具体目标3：我们将描述ET和LT在炭疽病早期和晚期对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.