α-Toxin Induces Platelet Aggregation and Liver Injury during Staphylococcus aureus Sepsis.
α-Toxin Induces Platelet Aggregation and Liver Injury during Staphylococcus aureus Sepsis.
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DOI：
10.1016/j.chom.2018.06.017
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发表时间：
2018-08-08
影响因子：
30.3
通讯作者：
Kubes P
中科院分区：
文献类型：
--
作者：
Surewaard BGJ;Thanabalasuriar A;Zeng Z;Tkaczyk C;Cohen TS;Bardoel BW;Jorch SK;Deppermann C;Bubeck Wardenburg J;Davis RP;Jenne CN;Stover KC;Sellman BR;Kubes P
在脓毒症期间，小血管可能会被大的血小板聚集物堵塞，而这些大的血小板聚集物的病因尚不清楚。在金黄色葡萄球菌感染期间，脓毒症的严重程度与细菌α毒素(α-溶血素，AT)通过不清楚的机制联系在一起。在这项研究中，我们可视化了微循环中的血管内事件，发现静脉注射AT诱导了血小板的快速聚集，在微循环中形成了动态的微血栓。这些聚集体滞留在肝窦和肾小球内，导致多器官功能障碍。急性葡萄球菌感染导致大多数细菌被肝巨噬细胞隔离。最初，血小板被招募到这些巨噬细胞中，帮助根除金黄色葡萄球菌。然而，在以后的时间点上，AT会导致整个肝脏的异常和破坏性血栓形成。使用AT中和抗体(MEDI4893*)治疗可防止血小板聚集和随后的肝损伤，而不影响最初和有益的血小板募集。因此，AT中和可能是对抗葡萄球菌诱导的血管内凝血和器官功能障碍的一种有前途的方法。葡萄球菌败血症常导致血小板减少和多器官功能障碍。使用活体成像，Surewaard等人。发现阿尔法毒素(AT)直接针对血小板，导致循环中的有害聚集。葡萄球菌性脓毒症期间中和AT不会干扰有益的血小板反应，同时预防微血管功能障碍和血栓形成。
During sepsis, small blood vessels can become occluded by large platelet aggregates of poorly understood etiology. During Staphylococcal aureus infection, sepsis severity is linked to the bacterial alpha toxin (α-hemolysin, AT) through unclear mechanisms. In this study, we visualized intravascular events in the microcirculation and found that intravenous AT injection induces rapid platelet aggregation, forming dynamic micro-thrombi in the microcirculation. These aggregates are retained in the liver sinusoids and kidney glomeruli, causing multi-organ dysfunction. Acute staphylococcal infection results in sequestration of most bacteria by liver macrophages. Platelets are initially recruited to these macrophages and help eradicate S. aureus. However, at later time points, AT causes aberrant and damaging thrombosis throughout the liver. Treatment with an AT neutralizing antibody (MEDI4893*) prevents platelet aggregation and subsequent liver damage, without affecting the initial and beneficial platelet recruitment. Thus, AT neutralization may represent a promising approach to combat staphylococcal-induced intravascular coagulation and organ dysfunction. Staphylococcal sepsis often results in thrombocytopenia and multi-organ dysfunction. Using intravital imaging, Surewaard et al. discovered that alpha-toxin (AT) directly targets platelets resulting in detrimental aggregation in the circulation. Neutralizing AT during staphylococcal sepsis does not interfere with beneficial platelet responses, while preventing microvascular dysfunction and thrombosis.
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