Department of Molecular Genetics and Infection Biology, Interfaculty Institute for Genetics and Functional Genomics, Center for Functional Genomics of Microbes, University of Greifswald, Greifswald, Germany.
Department of Transfusion Medicine, Institute of Immunology and Transfusion Medicine, University Medicine Greifswald, Greifswald, Germany.
J Thromb Haemost. 2022 Jun;20(6):1464-1475. doi: 10.1111/jth.15703. Epub 2022 Mar 27.
Toxins are key virulence determinants of pathogens and can impair the function of host immune cells, including platelets. Insights into pathogen toxin interference with platelets will be pivotal to improve treatment of patients with bacterial bloodstream infections.
In this study, we deciphered the effects of Staphylococcus aureus toxins α-hemolysin, LukAB, LukDE, and LukSF on human platelets and compared the effects with the pore forming toxin pneumolysin of Streptococcus pneumoniae. Activation of platelets and loss of platelet function were investigated by flow cytometry, aggregometry, platelet viability, fluorescence microscopy, and intracellular calcium release. Thrombus formation was assessed in whole blood.
α-hemolysin (Hla) is known to be a pore-forming toxin. Hla-induced calcium influx initially activates platelets as indicated by CD62P and αIIbβ3 integrin activation, but also induces finally alterations in the phenotype of platelets. In contrast to Hla and pneumolysin, S. aureus bicomponent pore-forming leukocidins LukAB, LukED, and LukSF do not bind to platelets and had no significant effect on platelet activation and viability. The presence of small amounts of Hla (0.2 µg/ml) in whole blood abrogates thrombus formation indicating that in systemic infections with S. aureus the stability of formed thrombi is impaired. Damage of platelets by Hla was not neutralized by intravenous immune globulins.
Our findings might be of clinical relevance for S. aureus induced endocarditis. Stabilizing the aortic-valve thrombi by inhibiting Hla-induced impairment of platelets might reduce the risk for septic (micro-)embolization.
毒素是病原体的关键毒力决定因素，可损害宿主免疫细胞的功能，包括血小板。深入了解病原体毒素对血小板的干扰作用，对于改善细菌血流感染患者的治疗至关重要。
在这项研究中，我们解析了金黄色葡萄球菌毒素 α-溶血素、LukAB、LukDE 和 LukSF 对人血小板的影响，并将其与肺炎链球菌的成孔毒素肺炎球菌溶血素进行了比较。通过流式细胞术、聚集测定法、血小板活力、荧光显微镜和细胞内钙释放来研究血小板的激活和血小板功能丧失。在全血中评估血栓形成。
α-溶血素（Hla）是一种已知的成孔毒素。Hla 诱导的钙内流最初通过 CD62P 和 αIIbβ3 整合素激活来激活血小板，但也最终导致血小板表型发生变化。与 Hla 和肺炎球菌溶血素不同，金黄色葡萄球菌双组分成孔白细胞毒素 LukAB、LukED 和 LukSF 不与血小板结合，对血小板激活和活力没有显著影响。全血中存在少量 Hla（0.2μg/ml）可阻止血栓形成，表明金黄色葡萄球菌全身感染会损害已形成的血栓的稳定性。静脉注射免疫球蛋白不能中和 Hla 对血小板的损伤。
我们的发现可能与金黄色葡萄球菌引起的心内膜炎具有临床相关性。通过抑制 Hla 诱导的血小板损伤来稳定主动脉瓣血栓可能会降低脓毒性（微）栓塞的风险。
