Department of Medicine, Pulmonary, Critical Care & Sleep Medicine, the University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
Department of Biostatistics, Virginia Commonwealth University, Richmond, VA 23298, USA.
Toxins (Basel). 2020 Jul 20;12(7):464. doi: 10.3390/toxins12070464.
, the causative agent of inhalation anthrax, is a serious concern as a bioterrorism weapon. The vegetative form produces two exotoxins: Lethal toxin (LT) and edema toxin (ET). We recently characterized and compared six human airway and alveolar-resident phagocyte (AARP) subsets at the transcriptional and functional levels. In this study, we examined the effects of LT and ET on these subsets and human leukocytes. AARPs and leukocytes do not express high levels of the toxin receptors, tumor endothelium marker-8 (TEM8) and capillary morphogenesis protein-2 (CMG2). Less than 20% expressed surface TEM8, while less than 15% expressed CMG2. All cell types bound or internalized protective antigen, the common component of the two toxins, in a dose-dependent manner. Most protective antigen was likely internalized via macropinocytosis. Cells were not sensitive to LT-induced apoptosis or necrosis at concentrations up to 1000 ng/mL. However, toxin exposure inhibited spore internalization. This inhibition was driven primarily by ET in AARPs and LT in leukocytes. These results support a model of inhalation anthrax in which spores germinate and produce toxins. ET inhibits pathogen phagocytosis by AARPs, allowing alveolar escape. In late-stage disease, LT inhibits phagocytosis by leukocytes, allowing bacterial replication in the bloodstream.
炭疽芽孢杆菌是吸入性炭疽的病原体，作为一种生物恐怖主义武器，令人严重关切。营养体产生两种外毒素：致死毒素（LT）和水肿毒素（ET）。我们最近在转录和功能水平上对六种人类气道和肺泡驻留吞噬细胞（AARP）亚群进行了表征和比较。在这项研究中，我们研究了 LT 和 ET 对这些亚群和人类白细胞的影响。AARPs 和白细胞不表达高水平的毒素受体，肿瘤内皮标记物 8（TEM8）和毛细血管形态发生蛋白 2（CMG2）。只有不到 20%的细胞表达表面 TEM8，而不到 15%的细胞表达 CMG2。所有细胞类型都以剂量依赖的方式结合或内化保护性抗原，这是两种毒素的共同成分。大多数保护性抗原可能通过巨胞饮作用内化。在高达 1000ng/mL 的浓度下，细胞对 LT 诱导的凋亡或坏死不敏感。然而，毒素暴露抑制了孢子的内化。这种抑制主要由 ET 在 AARPs 中驱动，由 LT 在白细胞中驱动。这些结果支持吸入性炭疽的一种模型，其中孢子发芽并产生毒素。ET 抑制 AARPs 吞噬病原体，允许肺泡逃逸。在疾病晚期，LT 抑制白细胞的吞噬作用，允许细菌在血液中复制。
