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Abstract：
Panton-Valentine Leukocidin (PVL) is a bicomponent leukotoxin produced by 3%-10% of clinical Staphylococcus aureus (SA) strains involved in the severity of hospital and community-acquired infections. Although PVL was long known as a pore-forming toxin, recent studies have challenged the formation of a pore at the plasma membrane, while its endocytosis and the exact mode of action remain to be defined. In vitro immunolabeling of human neutrophils shows that Neutrophil Extracellular Traps (NETosis) is triggered by the action of purified PVL, but not by Gamma hemolysin CB (HlgCB), a structurally similar SA leukotoxin. PVL causes the ejection of chromatin fibers (NETs) decorated with antibacterial peptides independently of the NADPH oxidase oxidative burst. Leukotoxin partially colocalizes with mitochondria and enhances the production of reactive oxygen species from these organelles, while showing an increased autophagy, which results unnecessary for NETs ejection. PVL NETosis is elicited through Ca2+ -activated SK channels and Myeloperoxidase activity but is abolished by Allopurinol pretreatment of neutrophils. Moreover, massive citrullination of the histone H3 is performed by peptidyl arginine deiminases. Inhibition of this latter enzymes fails to abolish NET extrusion. Unexpectedly, PVL NETosis does not seem to involve Src kinases, which is the main kinase family activated downstream the binding of PVL F subunit to CD45 receptor, while the specific kinase pathway differs from the NADPH oxidase-dependent NETosis. PVL alone causes a different and specific form of NETosis that may rather represent a bacterial strategy conceived to disarm and disrupt the immune response, eventually allowing SA to spread.
摘要：
Panton-Valentine白细胞抑制素（PVL）是一种双组分白细胞毒素，由3％-10％的临床金黄色葡萄球菌（SA）菌株产生，涉及医院和社区获得性感染的严重程度。尽管PVL长期以来被认为是一种成孔毒素，最近的研究挑战了质膜上孔的形成，而其内吞作用和确切的作用方式仍有待定义。人中性粒细胞的体外免疫标记表明，中性粒细胞细胞外陷阱（NETosis）是由纯化的PVL的作用触发的，但不是通过γ溶血素CB（HlgCB），一种结构相似的SA白细胞毒素。PVL引起用抗菌肽修饰的染色质纤维（NETs）的喷射，而与NADPH氧化酶的氧化爆发无关。白细胞毒素与线粒体部分共定位，并增强这些细胞器中活性氧的产生，同时显示自噬增加，这导致NET弹射不必要的结果。PVLNETosis是通过Ca2激活的SK通道和髓过氧化物酶活性引起的，但被别嘌呤醇预处理的中性粒细胞消除。此外，组蛋白H3的大量瓜氨酸化通过肽基精氨酸脱亚胺酶进行。对后一种酶的抑制不能消除NET挤出。出乎意料的是,PVLNETosis似乎不涉及Src激酶，它是PVLF亚基与CD45受体结合下游激活的主要激酶家族，而特异性激酶途径不同于NADPH氧化酶依赖性NETosis。单独的PVL会导致一种不同的特定形式的NETosis，这可能代表了一种细菌策略，旨在解除和破坏免疫反应。最终允许SA传播。
