Alileche Abdelkrim, Serfass Evan R, Muehlbauer Stefan M, Porcelli Steven A, Brojatsch Jürgen
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA.
PLoS Pathog. 2005 Oct;1(2):e19. doi: 10.1371/journal.ppat.0010019. Epub 2005 Oct 28.
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.
许多病原体已经获得了对抗免疫反应的策略。炭疽芽孢杆菌通过释放炭疽致死毒素（LT）干扰宿主防御，该毒素可使丝裂原活化蛋白激酶途径失活，导致树突状细胞（DCs）和T淋巴细胞对免疫刺激无反应。然而，这些细胞类型被认为对LT杀伤具有抗性。在此我们表明，LT在体外可杀死原代人DCs，在体外和体内可杀死小鼠DCs。LT介导的小鼠DCs杀伤动力学以及诱导的细胞死亡途径取决于遗传背景：LT在源自BALB/c的DCs中引发快速坏死，在源自C57BL/6的DCs中引发缓慢凋亡。这分别与注射LT的BALB/c和C57BL/6小鼠的快速和缓慢死亡一致。我们提供证据表明炭疽LT通过特异性靶向DCs损害适应性免疫。这可能代表了该细菌的一种免疫逃避策略，并有助于炭疽病的进展。我们还确定遗传背景决定了LT诱导的是凋亡还是坏死。最后，LT对源自C57BL/6的DCs的杀伤情况与对人DCs的杀伤情况相似，这表明与典型的BALB/c巨噬细胞相比，C57BL/6 DCs是更适合人类炭疽研究的模型系统。
