Bacillus anthracis toxins inhibit human neutrophil NADPH oxidase activity
Bacillus anthracis toxins inhibit human neutrophil NADPH oxidase activity
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DOI：
10.4049/jimmunol.176.12.7557
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发表时间：
2006-06-15
影响因子：
4.4
通讯作者：
Bokoch, Gary M.
中科院分区：
文献类型：
--
作者：
Crawford, Matthew A.;Aylott, Caroline V.;Bokoch, Gary M.
炭疽杆菌是炭疽病的病原体，是一种革兰氏阳性、孢子形成细菌。B。炭疽的毒力主要归因于分泌的三重AB型毒素，其由命名为保护性Ag（PA）、致死因子和水肿因子的三种蛋白质组成。PA与毒素的酶促部分、金属蛋白酶致死因子和/或腺苷酸环化酶水肿因子组装，分别产生致死毒素（LTx）和水肿毒素（ETx）。这些毒素通过PA与特定细胞表面受体的相互作用进入细胞。炭疽毒素的作用是抑制先天免疫反应，鉴于人类中性粒细胞在先天免疫中的重要性，它们可能是炭疽毒素的相关靶点。我们详细研究了B的影响。炭疽毒素对原代人中性粒细胞产生超氧化物的影响。LTx和ETx对fMLP（和C5 a）受体介导的超氧化物产生都表现出明显的抑制作用，但对PMA非受体依赖性超氧化物产生没有影响。这些抑制作用不能通过诱导中性粒细胞死亡或刺激受体水平的变化来解释。使用全细胞和无细胞系统对NADPH氧化酶调节的分析表明，毒素不对NADPH氧化酶组分产生直接作用，而是通过其各自的作用，MAPK信号传导（LTx）的抑制和细胞内cAMP（ETx）的升高，来抑制介导NADPH氧化酶组装和/或活化的上游信号传导组分。我们的研究结果表明，炭疽毒素有效地抑制人类嗜热菌介导的先天免疫，抑制他们的能力，产生超氧化物的细菌杀伤。
Bacillus anthracis, the causative agent of anthrax, is a Gram-positive, spore-forming bacterium. B. anthracis virulence is ascribed mainly to a secreted tripartite AB-type toxin composed of three proteins designated protective Ag (PA), lethal factor, and edema factor. PA assembles with the enzymatic portions of the toxin, the metalloprotease lethal factor, and/or the adenylate cyclase edema factor, to generate lethal toxin (LTx) and edema toxin (ETx), respectively. These toxins enter cells through the interaction of PA with specific cell surface receptors. The anthrax toxins act to suppress innate immune responses and, given the importance of human neutrophils in innate immunity, they are likely relevant targets of the anthrax toxin. We have investigated in detail the effects of B. anthracis toxin on superoxide production by primary human neutrophils. Both LTx and ETx exhibit distinct inhibitory effects on fMLP (and C5a) receptor-mediated superoxide production', but have no effect on PMA nonreceptor-dependent superoxide production. These inhibitory effects cannot be accounted for by induction of neutrophil death, or by changes in stimulatory receptor levels. Analysis of NADPH oxidase regulation using whole cell and cell-free systems suggests that the toxins do not exert direct effects on NADPH oxidase components, but rather act via their respective effects, inhibition of MAPK signaling (LTx), and elevation of intracellular cAMP (ETx), to inhibit upstream signaling components mediating NADPH oxidase assembly and/or activation. Our results demonstrate that anthrax toxins effectively suppress human neutrophil-mediated innate immunity by inhibiting their ability to generate superoxide for bacterial killing.