Fibronectin-binding proteins of Staphylococcus aureus mediate activation of human platelets via fibrinogen and fibronectin bridges to integrin GPIIb/IIIa and IgG binding to the FcγRIIa receptor
Fibronectin-binding proteins of Staphylococcus aureus mediate activation of human platelets via fibrinogen and fibronectin bridges to integrin GPIIb/IIIa and IgG binding to the FcγRIIa receptor
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DOI：
10.1111/j.1365-2958.2005.04922.x
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发表时间：
2006-01-01
影响因子：
3.6
通讯作者：
Foster, TJ
中科院分区：
文献类型：
--
作者：
Fitzgerald, JR;Loughman, A;Foster, TJ
金黄色葡萄球菌是感染性心内膜炎（IE）的主要原因。S.金黄色葡萄球菌引起的聚集和血栓形成是IE发病机制中的重要步骤。在这里，我们报告，纤维蛋白原/纤连蛋白结合蛋白FnBPA和FnBPB是S.金黄色葡萄球菌从指数生长期。FnBPA的截短衍生物，呈现纤维蛋白原结合A结构域或纤连蛋白结合BCD区域，当在S.金黄色葡萄球菌或乳酸乳球菌，表明两种不同的激活机制。FnBPA促进的血小板活化是由A结构域和BCD结构域之间的纤维蛋白原和纤连蛋白桥分别介导的，与静息血小板上整合素GPIIb/IIIa的低亲和力形式。识别FnBPA A结构域或FnBPA BCD结构域与纤连蛋白之间的复合物的抗体对于分别表达A结构域或BCD结构域的细菌促进的活化是必需的。血小板上Fc γ RIIa IgG受体特异性单克隆抗体（IV-3）抑制活化。我们提出，表达FnBP的细菌对静止血小板的激活涉及通过（i）纤连蛋白和纤维蛋白原与GPIIb/IIIa的低亲和力形式相互作用和（ii）通过与血小板Fc受体Fc γ RIIa接合的FnBP特异性抗体在细菌细胞和血小板表面之间形成桥梁。S.来自生长的指数期和稳定期的金黄色葡萄球菌临床IE分离物被单克隆抗体IV-3完全抑制，这表明IgG-Fc γ RIIa相互作用对于由该生物体介导的血小板活化是至关重要的。这为开发抗血管感染的治疗方法提供了新的途径。
Staphylococcus aureus is a leading cause of infective endocarditis (IE). Platelet activation promoted by S. aureus resulting in aggregation and thrombus formation is an important step in the pathogenesis of IE. Here, we report that the fibrinogen/fibronectin-binding proteins FnBPA and FnBPB are major platelet-activating factors on the surface of S. aureus from the exponential phase of growth. Truncated derivatives of FnBPA, presenting either the fibrinogen-binding A domain or the fibronectin-binding BCD region, each promoted platelet activation when expressed on the surface of S. aureus or Lactococcus lactis, indicating two distinct mechanisms of activation. FnBPA-promoted platelet activation is mediated by fibrinogen and fibronectin bridges between the A domain and the BCD domains, respectively, to the low affinity form of the integrin GPIIb/IIIa on resting platelets. Antibodies recognizing the FnBPA A domain or the complex between the FnBPA BCD domains and fibronectin were essential for activation promoted by bacteria expressing the A domain or the BCD domain respectively. Activation was inhibited by a monoclonal antibody (IV-3) specific for the Fc gamma RIIa IgG receptor on platelets. We propose that the activation of quiescent platelets by bacteria expressing FnBPs involves the formation of a bridge between the bacterial cell and the platelet surface by (i) fibronectin and fibrinogen interacting with the low affinity form of GPIIb/IIIa and (ii) by antibodies specific to FnBPs that engage the platelet Fc receptor Fc gamma RIIa. Platelet activation by S. aureus clinical IE isolates from both the exponential and stationary phases of growth was completely inhibited by monoclonal antibody IV-3 suggesting that the IgG-Fc gamma RIIa interaction is of fundamental importance for platelet activation mediated by this organism. This suggests new avenues for development of therapeutics against vascular infections.