Staphylococcus aureus Panton-Valentine leukocidin directly targets mitochondria and induces Bax-independent apoptosis of human neutrophils
Staphylococcus aureus Panton-Valentine leukocidin directly targets mitochondria and induces Bax-independent apoptosis of human neutrophils
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DOI：
10.1172/jci22684
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发表时间：
2005-11-01
影响因子：
15.9
通讯作者：
Genestier, L
中科院分区：
文献类型：
--
作者：
Genestier, AL;Michallet, MC;Genestier, L
潘顿-瓦伦丁杀白素(PVL)是一种由金黄色葡萄球菌分泌的致孔毒素，最近被认为与坏死性肺炎有关。在本研究中，我们报道了在体外，PVL通过坏死或凋亡诱导多形核细胞死亡，这取决于PVL的浓度。PVL诱导的细胞凋亡与线粒体动态平衡的快速破坏和caspase-9、caspase-3的激活有关，提示PVL诱导的细胞凋亡主要由线粒体途径介导。中性粒细胞暴露于PVL可导致该毒素的线粒体定位，而Bax仍定位于胞浆中。在分离的线粒体中加入PVL可诱导细胞色素c和Smac/DIABLO蛋白的释放。因此，我们认为PVL属于致孔毒素家族，它可能通过在线粒体外膜上形成孔洞而在线粒体水平发挥作用。此外，在坏死性肺炎患者肺组织切片中检测到PVL的两种成分之一的Luks-PV，并伴有DNA片段化，提示PVL可在体内诱导细胞凋亡，从而直接参与坏死性肺炎的病理生理过程。
Panton-Valentine leukocidin (PVL) is a pore-forming toxin secreted by Staphylococcus aureus that has recently been associated with necrotizing pneumonia. In the present study, we report that in vitro, PVL induces polymorphonuclear cell death by necrosis or by apoptosis, depending on the PVL concentration. PVL-induced apoptosis was associated with a rapid disruption of mitochondrial homeostasis and activation of caspase-9 and caspase-3, suggesting that PVL-induced apoptosis is preferentially mediated by the mitochondrial pathway. Polymorphonuclear cell exposure to PVL leads to mitochondrial localization of the toxin, whereas Bax, 1 of the 2 essential proapoptotic members of the Bcl-2 family, was still localized in the cytosol. Addition of PVL to isolated mitochondria induced the release of the apoptogenic proteins cytochrome c and Smac/ DIABLO. Therefore, we suggest that PVL, which belongs to the pore-forming toxin family, could act at the mitochondrion level by creating pores in the mitochondrial outer membrane. Furthermore, LukS-PV, 1 of the 2 components of PVL, was detected in lung sections of patients with necrotizing pneumonia together with DNA fragmentation, suggesting that PVL induces apoptosis in vivo and thereby is directly involved in the pathophysiology of necrotizing pneumonia.