Inhibition of major integrin αVβ3 reduces Staphylococcus aureus attachment to sheared human endothelial cells.
BACKGROUND: Vascular endothelial dysfunction with associated oedema and organ failure is one of the hallmarks of sepsis. While a large number of microorganisms can cause sepsis, Staphylococcus aureus is one of the primary etiological agents. Currently there are no approved specific treatments for sepsis and therefore the initial management bundle focuses on cardiorespiratory resuscitation and mitigation against the immediate threat of uncontrolled infection. The continuous emergence of antibiotic resistant strains of bacteria urges the development of new therapeutic approaches for this disease.
OBJECTIVE: The objective of this study was to identify the molecular mechanisms leading to endothelial dysfunction as a result of Staphylococcus aureus binding.
METHODS: Stahpylococcus aureus Newman and clumping factor A-deficient binding to endothelium were measured in vitro and in the mesenteric circulation of C57Bl/6 mice. The effect of the αVβ3 blocker, cilengitide, on bacterial binding, endothelial VE-cadherin expression, apoptosis, proliferation and permeability were assessed.
RESULTS: Here we show that the major Staphylococcus aureus cell wall protein clumping factor A binds to endothelial cell integrin αVβ3 in the presence of fibrinogen. This interaction results in disturbances in barrier function mediated by VE-cadherin in endothelial cell monolayers and ultimately cell death by apoptosis. Using a low concentration of cilengitide, ClfA binding to αVβ3 was significantly inhibited both in vitro and in vivo. Moreover, preventing Staphylococcus aureus from attaching to αVβ3 resulted in a significant reduction in endothelial dysfunction following infection.
CONCLUSION: Inhibition of Staphylococcus aureus ClfA binding to endothelial cell αVβ3 using cilengitide prevents endothelial dysfunction. This article is protected by copyright. All rights reserved.
Science Foundation Ireland. HEA/PRTLI.
CommentsThis is the pre-peer reviewed version of the following article: McDonnell CJ, Garciarena CD, Watkin RL, McHale TM, McLoughlin A, Claes J, Verhamme P, Cummins PM, Kerrigan SW. Inhibition of major integrin αVβ3 reduces Staphylococcus aureus attachment to sheared human endothelial cells. Journal of Thrombosis and Haemostasis. 2016;14(12):2536-2547 which has been published in final form at DOI: 10.1111/jth.13501This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.
Published CitationMcDonnell CJ, Garciarena CD, Watkin RL, McHale TM, McLoughlin A, Claes J, Verhamme P, Cummins PM, Kerrigan SW. Inhibition of major integrin αVβ3 reduces Staphylococcus aureus attachment to sheared human endothelial cells. Journal of Thrombosis and Haemostasis. 2016;14(12):2536-2547
- Irish Centre for Vascular Biology
- School of Pharmacy and Biomolecular Sciences