Pulmonary and Critical Care Division of the Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
Infect Immun. 2012 Dec;80(12):4374-87. doi: 10.1128/IAI.01011-12. Epub 2012 Oct 1.
The lung is the site of entry for Bacillus anthracis in inhalation anthrax, the deadliest form of the disease. Bacillus anthracis produces virulence toxins required for disease. Alveolar macrophages were considered the primary target of the Bacillus anthracis virulence factor lethal toxin because lethal toxin inhibits mouse macrophages through cleavage of MEK signaling pathway components, but we have reported that human alveolar macrophages are not a target of lethal toxin. Our current results suggest that, unlike human alveolar macrophages, the cells lining the respiratory units of the lung, alveolar epithelial cells, are a target of lethal toxin in humans. Alveolar epithelial cells expressed lethal toxin receptor protein, bound the protective antigen component of lethal toxin, and were subject to lethal-toxin-induced cleavage of multiple MEKs. These findings suggest that human alveolar epithelial cells are a target of Bacillus anthracis lethal toxin. Further, no reduction in alveolar epithelial cell viability was observed, but lethal toxin caused actin rearrangement and impaired desmosome formation, consistent with impaired barrier function as well as reduced surfactant production. Therefore, by compromising epithelial barrier function, lethal toxin may play a role in the pathogenesis of inhalation anthrax by facilitating the dissemination of Bacillus anthracis from the lung in early disease and promoting edema in late stages of the illness.
肺是吸入性炭疽病（炭疽病中最致命的形式）中炭疽杆菌进入人体的部位。炭疽杆菌产生致病毒素是疾病发生的必要条件。肺泡巨噬细胞被认为是炭疽杆菌致死毒素的主要靶标，因为致死毒素通过切割 MEK 信号通路成分来抑制小鼠巨噬细胞，但我们已经报告称，人类肺泡巨噬细胞不是致死毒素的靶标。我们目前的研究结果表明，与人类肺泡巨噬细胞不同，肺部呼吸单位的细胞——肺泡上皮细胞，是人类致死毒素的靶标。肺泡上皮细胞表达致死毒素受体蛋白，结合致死毒素的保护性抗原成分，并受到致死毒素诱导的多种 MEK 的切割。这些发现表明，人类肺泡上皮细胞是炭疽杆菌致死毒素的靶标。此外，未观察到肺泡上皮细胞活力降低，但致死毒素导致肌动蛋白重排并损害桥粒形成，这与屏障功能受损以及表面活性剂产生减少一致。因此，通过损害上皮屏障功能，致死毒素可能通过促进炭疽杆菌从肺部早期疾病中的传播，并促进疾病后期的水肿，在吸入性炭疽病的发病机制中发挥作用。
