Key tissue targets responsible for anthrax-toxin-induced lethality

摘要

炭疽杆菌产生两种毒素—炭疽致命毒素和水 肿毒素，它们被与captor相关的保护性抗原定 向到组织中。这两种毒素在发病机制中起必不 可少的作用，但我们对这些作用却了解很少。 在这项研究中，Shihui Liu及同事培育出缺少 细胞类型特定性炭疽毒素受体"毛细形态发生 蛋白-2" (CMG2)的小鼠,并利用它们发现， 这两种毒素以不同细胞类型为目标。与以前的 观点相反的是，内皮细胞并不是其中任何一种 毒素的关键目标。相反，致命毒素以心肌细胞 和血管平滑肌细胞为目标，而水肿毒素以肝细 胞为目标。认识到炭疽毒素专门以心血管系统 和肝脏为目标，可能有助于提出在人类炭疽感 染中限制组织损伤和提高存活率的辅助性治疗 方法。%Bacillus anthracis, the causative agent of anthrax disease, is lethal owing to the actions of two exotoxins: anthrax lethal toxin (LT) and oedema toxin (ET). The key tissue targets responsible for the lethal effects of these toxins are unknown. Here we generated cell-type-specific anthrax toxin receptor capillary morphogenesis protein-2 (CMG2)-null mice and cell-type-specific CMG2-expressing mice and challenged them with the toxins. Our results show that lethality induced by LT and ET occurs through damage to distinct cell types; whereas targeting cardiomyocytes and vascular smooth muscle cells is required for LT-induced mortality, ET-induced lethality occurs mainly through its action in hepatocytes. Notably, and in contradiction to what has been previously postulated, targeting of endothelial cells by either toxin does not seem to contribute significantly to lethality. Our findings demonstrate that B. anthracis has evolved to use LT and ET to induce host lethality by coordinately damaging two distinct vital systems.