Inhibition of major integrin αVβ3 reduces Staphylococcus aureus attachment to sheared human endothelial cells

Background: Vascular endothelial dysfunction with associated edema and organ failure is one of the hallmarks of sepsis. Although a large number of microorganisms can cause sepsis, Staphylococcus aureus (S. aureus) is one of the primary etiologic agents. Currently, there are no approved specific treatments for sepsis, and the initial management bundle is therefore focused on cardiorespiratory resuscitation and mitigation of the immediate threat of uncontrolled infection. The continuous emergence of antibiotic-resistant strains of bacteria necessitates the development of new therapeutic approaches for this disease. Objective: To identify the molecular mechanisms leading to endothelial dysfunction as a result of S. aureus binding. Methods: Binding of wild type and Clumping factor A (ClfA) deficient S. aureus Newman to the endothelium was measured in vitro and in the mesenteric circulation of C57Bl/6 mice. The effects of the alpha(V)beta(3) blocker-cilengitide-on bacterial binding, endothelial VE-cadherin expression, apoptosis, proliferation and permeability were assessed. Results: The major S. aureus cell wall protein ClfA bound to endothelial cell alpha(V)beta(3) in the presence of fibrinogen. This interaction resulted in disturbances in barrier function mediated by VE-cadherin in endothelial cell monolayers, and ultimately cell death by apoptosis. With a low concentration of cilengitide, ClfA binding to alpha(V)beta(3) was significantly inhibited both in vitro and in vivo. Moreover, preventing S. aureus from attaching to alpha(V)beta(3) resulted in a significant reduction in endothelial dysfunction following infection. Conclusion: Inhibition of S. aureus ClfA binding to endothelial cell alpha(V)beta(3) by cilengitide prevents endothelial dysfunction.