Staphylococcus aureus adhesion in endovascular infections is controlled by the ArlRS-MgrA signaling cascade
Staphylococcus aureus adhesion in endovascular infections is controlled by the ArlRS-MgrA signaling cascade
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DOI：
10.1371/journal.ppat.1007800
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发表时间：
2019-05-01
期刊：
影响因子：
6.7
通讯作者：
Horswill, Alexander R.
中科院分区：
文献类型：
--
作者：
Kwiecinski, Jakub M.;Crosby, Heidi A.;Horswill, Alexander R.
金黄色葡萄球菌是血管内感染的主要原因。这种细菌性病原体使用多种表面粘附素在血液中聚集并粘附于血管壁，导致内皮损伤、血管内赘生物和继发性感染灶的发展以及总体疾病进展。在这项工作中，我们描述了一个新的战略使用的S。金黄色葡萄球菌通过ArlRS双组分调节系统及其下游效应物MgrA的活性来控制粘附和凝集。利用体外细胞分析和单细胞原子力显微镜的组合，我们证明了这种ArlRS-MgrA级联的失活抑制S。金黄色葡萄球菌与大量相关宿主分子（纤维蛋白原、纤连蛋白、血管性血友病因子、胶原蛋白）的粘附、其与纤维蛋白原的凝集以及其与人内皮细胞和血管结构的附着。这对S.金黄色葡萄球菌粘附在低剪切环境中、在生理水平的剪切应力中以及在小鼠模型中的体内是明显的。这些作用可能是由ArlRS-MgrA级联的失活引起的巨大表面蛋白Ebh、SraP和SasG的去抑制介导的。在我们的体外试验中，这些巨大的蛋白质共同屏蔽了其他表面粘附素的功能，并削弱了它们与同源配体的结合。最后，我们通过鉴定ArlRS信号传导的小分子抑制剂证明了ArlRS-MgrA调节级联是可药物化的靶点。我们的研究结果为药物治疗和预防S.通过靶向ArlRS-MgrA调节系统来治疗金黄色葡萄球菌血管内感染。
Staphylococcus aureus is a leading cause of endovascular infections. This bacterial pathogen uses a diverse array of surface adhesins to clump in blood and adhere to vessel walls, leading to endothelial damage, development of intravascular vegetations and secondary infectious foci, and overall disease progression. In this work, we describe a novel strategy used by S. aureus to control adhesion and clumping through activity of the ArlRS two-component regulatory system, and its downstream effector MgrA. Utilizing a combination of in vitro cellular assays, and single-cell atomic force microscopy, we demonstrated that inactivation of this ArlRS-MgrA cascade inhibits S. aureus adhesion to a vast array of relevant host molecules (fibrinogen, fibronectin, von Willebrand factor, collagen), its clumping with fibrinogen, and its attachment to human endothelial cells and vascular structures. This impact on S. aureus adhesion was apparent in low shear environments, and in physiological levels of shear stress, as well as in vivo in mouse models. These effects were likely mediated by the de-repression of giant surface proteins Ebh, SraP, and SasG, caused by inactivation of the ArlRS-MgrA cascade. In our in vitro assays, these giant proteins collectively shielded the function of other surface adhesins and impaired their binding to cognate ligands. Finally, we demonstrated that the ArlRS-MgrA regulatory cascade is a druggable target through the identification of a small-molecule inhibitor of ArlRS signaling. Our findings suggest a novel approach for the pharmacological treatment and prevention of S. aureus endovascular infections through targeting the ArlRS-MgrA regulatory system.