Anthrax lethal toxin-mediated killing of human and murine dendritic cells impairs the adaptive immune response.
Anthrax lethal toxin-mediated killing of human and murine dendritic cells impairs the adaptive immune response.
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炭疽致死的毒素介导的人和鼠树突状细胞杀死损害适应性免疫反应。
DOI：
10.1371/journal.ppat.0010019
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发表时间：
2005-10
期刊：
影响因子：
6.7
通讯作者：
Brojatsch, Jurgen
中科院分区：
文献类型：
--
作者：
Alileche, Abdelkrim;Serfass, Evan R;Muehlbauer, Stefan M;Porcelli, Steven A;Brojatsch, Jurgen
许多病原体已经获得了对抗免疫反应的策略。炭疽杆菌通过释放炭疽致死毒素（LT）干扰宿主防御，其使丝裂原活化蛋白激酶途径失活，使树突状细胞（DC）和T淋巴细胞对免疫刺激无应答。然而，这些细胞类型被认为是耐LT杀死。在这里，我们表明，LT杀死原代人DC在体外，和鼠DC在体外和体内。LT介导的小鼠DCs杀伤的动力学以及诱导的细胞死亡途径依赖于遗传背景：LT引发BALB/c衍生的DCs的快速坏死，以及C57 BL/6衍生的DCs的缓慢凋亡。这分别与LT注射BALB/c和C57 BL/6小鼠的快速和缓慢杀死一致。我们目前的证据表明，炭疽LT损害适应性免疫特异性靶向DC。这可能代表了细菌的免疫逃避策略，并有助于炭疽病的进展。我们还建立了遗传背景决定是否由LT诱导细胞凋亡或坏死。最后，杀死C57 BL/6衍生的DC由LT镜像的人DC，这表明C57 BL/6 DC代表一个更好的模型系统比原型BALB/c巨噬细胞的人炭疽。树突状细胞（DC）是特化的白色血细胞，其识别抗原并将抗原呈递给免疫细胞（T细胞），以产生靶向针对特定病原体的免疫应答。DC对于宿主抵抗感染至关重要。先前的研究表明，炭疽杆菌通过释放的毒素（致命毒素）的作用使许多免疫细胞（包括DC）丧失功能。在这里，作者表明致命毒素有效地杀死人和鼠DC。炭疽毒素杀死DCs的方式明显不同，并取决于其遗传背景。人DC以及源自鼠品系C57 BL/6的那些DC在72小时的过程中通过细胞凋亡或程序性细胞死亡的激活而死亡。然而，来自BALB/c小鼠的DC在毒素暴露后迅速死于坏死细胞死亡。由于人和C57 BL/6 DC对炭疽毒素具有相同的应答，C57 BL/6小鼠似乎为人炭疽提供了极好的模型。这项研究的结果表明，炭疽毒素对DC的特异性靶向损害了受感染宿主的免疫反应，作者认为这种策略促进了细菌的传播和疾病的进展。
Many pathogens have acquired strategies to combat the immune response. Bacillus anthracis interferes with host defenses by releasing anthrax lethal toxin (LT), which inactivates mitogen-activated protein kinase pathways, rendering dendritic cells (DCs) and T lymphocytes nonresponsive to immune stimulation. However, these cell types are considered resistant to killing by LT. Here we show that LT kills primary human DCs in vitro, and murine DCs in vitro and in vivo. Kinetics of LT-mediated killing of murine DCs, as well as cell death pathways induced, were dependent upon genetic background: LT triggered rapid necrosis in BALB/c-derived DCs, and slow apoptosis in C57BL/6-derived DCs. This is consistent with rapid and slow killing of LT-injected BALB/c and C57BL/6 mice, respectively. We present evidence that anthrax LT impairs adaptive immunity by specifically targeting DCs. This may represent an immune-evasion strategy of the bacterium, and contribute to anthrax disease progression. We also established that genetic background determines whether apoptosis or necrosis is induced by LT. Finally, killing of C57BL/6-derived DCs by LT mirrors that of human DCs, suggesting that C57BL/6 DCs represent a better model system for human anthrax than the prototypical BALB/c macrophages. Dendritic cells (DCs) are specialized white blood cells that identify and present antigens to immune cells, T cells, in order to mount an immune response targeted against specific pathogens. DCs are critical to a host's defense against infection. Previous work has shown that the anthrax bacterium disables many immune cells, including DCs, through the action of a released toxin, lethal toxin. Here the authors show that lethal toxin efficiently kills both human and murine DCs. The means by which DCs were killed by the anthrax toxin were notably distinct and dependent on their genetic background. Human DCs, as well as those derived from the murine strain C57BL/6, died over the course of 72 h via activation of apoptosis, or programmed cell death. DCs from BALB/c mice, however, died rapidly of a necrotic cell death following toxin exposure. As human and C57BL/6 DCs share an identical response to anthrax toxin, C57BL/6 mice appear to provide an excellent model for human anthrax. The study's findings suggest that specific targeting of DCs by the anthrax toxin impairs the immune response of the infected host, and the authors believe that this strategy promotes spread of the bacterium and disease progression.