Sherer Kevin, Li Yan, Cui Xizhong, Eichacker Peter Q
Critical Care Medicine Department, National Institutes of Health, Bethesda, MD 20892, USA.
Am J Respir Crit Care Med. 2007 Feb 1;175(3):211-21. doi: 10.1164/rccm.200608-1239CP. Epub 2006 Nov 9.
Recent research regarding the structure and function of Bacillus anthracis lethal (LeTx) and edema (ETx) toxins provides growing insights into the pathophysiology and treatment of shock with this lethal bacteria. These are both binary-type toxins composed of protective antigen necessary for their cellular uptake and either lethal or edema factors, the toxigenic moieties. The primary cellular receptors for protective antigen have been identified and constructed and key steps in the extracellular processing and internalization of the toxins clarified. Consistent with the lethal factor's primary action as an intracellular endopeptidase targeting mitogen-activated protein kinase kinases, growing evidence indicates that shock with this toxin does not result from an excessive inflammatory response. In fact, the potent immunosuppressive effects of LeTx may actually contribute to the establishment and persistence of infection. Instead, shock with LeTx may be related to the direct injurious effects of lethal factor on endothelial cell function. Despite the importance of LeTx, very recent studies show that edema factor, a potent adenyl cyclase, has the ability to make a substantial contribution to shock caused by B. anthracis and works additively with LeTx. Furthermore, ETx may contribute to the immunosuppressive effects of LeTx. Therapies under development that target several different steps in the cellular uptake and function of these two toxins have been effective in in vitro and in vivo systems. Understanding how best to apply these agents clinically and how they interact with conventional treatments should be goals for future research.
近期关于炭疽芽孢杆菌致死毒素（LeTx）和水肿毒素（ETx）的结构与功能的研究，为深入了解这种致命细菌所致休克的病理生理学及治疗方法提供了越来越多的见解。这两种都是二元型毒素，由细胞摄取所必需的保护性抗原以及致死因子或水肿因子（产毒部分）组成。保护性抗原的主要细胞受体已被鉴定和构建，毒素细胞外加工和内化的关键步骤也已明确。与致死因子作为靶向丝裂原活化蛋白激酶激酶的细胞内肽酶的主要作用一致，越来越多的证据表明，这种毒素所致休克并非源于过度的炎症反应。事实上，LeTx强大的免疫抑制作用可能实际上有助于感染的建立和持续存在。相反，LeTx所致休克可能与致死因子对内皮细胞功能的直接损伤作用有关。尽管LeTx很重要，但最近的研究表明，水肿因子作为一种强大的腺苷酸环化酶，有能力对炭疽芽孢杆菌所致休克做出重大贡献，并与LeTx协同作用。此外，ETx可能有助于LeTx的免疫抑制作用。正在研发的针对这两种毒素细胞摄取和功能中几个不同步骤的疗法，在体外和体内系统中均已显示有效。了解如何在临床上最佳应用这些药物以及它们如何与传统治疗相互作用，应成为未来研究的目标。
