Anthrax lethal toxin induces cell death-independent permeability in zebrafish vasculature
Anthrax lethal toxin induces cell death-independent permeability in zebrafish vasculature
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DOI：
10.1073/pnas.0712195105
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发表时间：
2008-02-19
影响因子：
11.1
通讯作者：
Chan, Joanne
中科院分区：
文献类型：
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作者：
Bolcome, Robert E., III;Sullivan, Sarah E.;Chan, Joanne
在人类炭疽病例、哺乳动物炭疽芽孢杆菌模型和注射炭疽毒素蛋白的动物中都有血管功能障碍的报道。为了检查炭疽致死毒素对完整血管的影响，我们开发了一个斑马鱼模型，允许在体内成像和评估血管和心血管功能。在数百个胚胎中监测的血管缺陷使我们能够确定导致循环功能障碍的表型进展的四个阶段。我们通过追踪注射毒素的胚胎中荧光微球的外渗，证明了内皮细胞渗透性增加是毒素作用的早期结果。如吖啶橙染色所示，致死性毒素未引起胚胎组织或血管中大量细胞死亡，注射致死性毒素的胚胎内皮细胞继续以正常速率分裂。血管通透性受到VEGF/血管通透性因子（VPF）信号通路的强烈影响，我们能够通过VEGFR功能的化学抑制剂减弱炭疽致死毒素的作用。我们的研究证明了血管通透性在炭疽致死毒素作用中的重要性，以及进一步研究人类炭疽病的心血管成分的必要性。
Vascular dysfunction has been reported in human cases of anthrax, in mammalian models of Bacillus anthracis, and in animals injected with anthrax toxin proteins. To examine anthrax lethal toxin effects on intact blood vessels, we developed a zebrafish model that permits in vivo imaging and evaluation of vasculature and cardiovascular function. Vascular defects monitored in hundreds of embryos enabled us to define four stages of phenotypic progression leading to circulatory dysfunction. We demonstrated increased endothelial permeability as an early consequence of toxin action by tracking the extravasation of fluorescent microspheres in toxin-injected embryos. Lethal toxin did not induce a significant amount of cell death in embryonic tissues or blood vessels, as shown by staining with acridine orange, and endothelial cells in lethal toxin-injected embryos continued to divide at the normal rate. Vascular permeability is strongly affected by the VEGF/vascular permeability factor (VPF) signaling pathway, and we were able to attenuate anthrax lethal toxin effects with chemical inhibitors of VEGFR function. Our study demonstrates the importance of vascular permeability in anthrax lethal toxin action and the need for further investigation of the cardiovascular component of human anthrax disease.