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PLoS Pathog. 2019 May 22;15(5):e1007800. doi: 10.1371/journal.ppat.1007800. eCollection 2019 May.

Staphylococcus aureus adhesion in endovascular infections is controlled by the ArlRS-MgrA signaling cascade.

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Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, United States of America.
Institute of Life Sciences, Université catholique de Louvain, Louvain-la-Neuve, Belgium.
Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, United States of America.
Department of Internal Medicine, University of Iowa, Iowa City, Iowa, United States of America.
Walloon Excellence in Life Sciences and Biotechnology (WELBIO), Wallonia, Belgium.
Department of Veterans Affairs Eastern Colorado Healthcare System, Denver, Colorado, United States of America.


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.

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