Clumping factor A, von Willebrand factor‐binding protein and von Willebrand factor anchor Staphylococcus aureus to the vessel wall

Abstract

Summary. Objective: When establishing endovascular infections, Staphylococcus aureus (S. aureus) overcomes shear forces of flowing blood by binding to von Willebrand factor (VWF). Staphylococcal VWF-binding protein (vWbp) interacts with VWF, but it is unknown how this secreted protein binds to the bacterial cell wall. We hypothesized that vWbp interacts with a staphylococcal surface protein, mediating the adhesion of S. aureus to VWF and vascular endothelium under shear stress. Methods: We studied the binding of S. aureus to vWbp, VWF and endothelial cells in a micro-parallel flow chamber using various mutants deficient in Sortase A (SrtA) and SrtA-dependent surface proteins, and Lactococcus lactis expressing single staphylococcal surface proteins. In vivo adhesion of bacteria was evaluated in the murine mesenteric circulation using real-time intravital vascular microscopy. Results: vWbp bridges the bacterial cell wall and VWF, allowing shear-resistant binding of S. aureus to inflamed or damaged endothelium. Absence of SrtA and Clumping factor A (ClfA) reduced adhesion of S. aureus to vWbp, VWF and activated endothelial cells. ADAMTS-13 and an anti-VWF A1 domain antibody, when combined, reduced S. aureus adhesion to activated endothelial cells by 90%. Selective overexpression of ClfA in the membrane of Lactococcus lactis enabled these bacteria to bind to VWF and activated endothelial cells but only in the presence of vWbp. Absence of ClfA abolished bacterial adhesion to the activated murine vessel wall. Conclusions: vWbp interacts with VWF and with the SrtA-dependent staphylococcal surface protein ClfA. The complex formed by VWF, secreted vWbp and bacterial ClfA anchors S. aureus to vascular endothelium under shear stress.

Force-Induced Strengthening of the Interaction between Staphylococcus aureus Clumping Factor B and Loricrin

“…During endovascular infections, S. aureus overcomes shear forces of flowing blood by attaching to von Willebrand factor (VWF) ( 34 , 35 ). Shear-resistant adhesion involves a secreted staphylococcal VWF-binding protein that simultaneously interacts with ClfA on the bacterial cell surface and with VWF on the vessel wall ( 36 ). These examples show that increased shear stress can promote the adhesion of S. aureus and that this force-sensitive adhesion involves CWA proteins.…”

Staphylococcus aureus, master manipulator of the human hemostatic system

“…Instead, VWbp enables the VWF binding at high shear rates, by binding in a shear‐dependent manner to the A1 domain . Although VWbp is a secreted molecule, it is bound to the cell wall via ClfA (Fig. ).…”

Staphylococcal Adhesion and Host Cell Invasion: Fibronectin-Binding and Other Mechanisms

“…Their N-terminal part contains a signal peptide for their secretion, followed by a ligand binding region mainly consisting of repeated sequences often rich in Serine. The mechanisms involving these proteins are Fn-independent: SdrD binds directly to Desmoglein 1 on the cell surface of keratinocytes and desquamated nasal cells ( Corrigan et al, 2009 ; Askarian et al, 2016 ); ClfA interacts directly with host cells or through fibrinogen bridges ( McDonnell et al, 2016 ; Claes et al, 2017 ); Atl seems to mediate S. aureus internalization via direct interactions with Hsc70 ( Hirschhausen et al, 2010 ); and SraP adheres to A549 cells through the salivary scavenger protein gp340 ( Yang et al, 2014 ) ( Figure 1C ). Note that the SdrD and Atl mechanisms require both bacterial and cellular activity as their efficiency depends on the expression of the bacterial and of the cellular interactor.…”