Abstract Number: OC 28.4
Meeting: ISTH 2021 Congress
Background: Acute vascular endothelial dysfunction is a central event in the pathogenesis of sepsis and leads to increasing vascular leak, tissue oedema and compromising regional perfusion in critical organs. The incidence of fungal infection in septic patients is only second to Staphylococcus aureus-induced sepsis, and is increasing at a rapid rate. The pathway in which fungi interact with endothelial cells is unknown.
Aims: The aim of this study is to elucidate the factors by which the leading fungal pathogen Candida albicans interacts with human vascular endothelial cells to result in disseminated candidiasis.
Methods: Fungal attachment to sheared cells was investigated using in-vitro binding assays. Vascular permeability were measured by transwell membrane assays. Expression of fungal proteins were studied with immunofluorescence, flow cytometry, and western blots.
Results: C. albicans attached to both static and sheared human endothelial cells (p<0.0001), and binding was significantly improved with the addition of plasma fibrinogen (p<0.05). Fungal adhesion was dose-dependently inhibited using the αVβ3 antagonist, Cilengitide (p<0.005). Through flow cytometry, we demonstrated that C. albicans expresses an integrin αVβ3-like protein on its surface. This suggests it binds directly to plasma fibrinogen and cross-links the fungus to human endothelial cell αVβ3. Fungal attachment resulted in endothelial barrier injury, as determined by loss of tight junction protein Vascular Endothelial cadherin, and an increase in permeability. During infection, yeast cells were unable to cause apoptosis, yet successfully induced VE-cadherin internalisation and downregulation within endothelial cells. However, blocking αVβ3 significantly restored VE-cadherin levels and barrier integrity.
Conclusions: Our data for the first time demonstrates a mechanism through which C. albicans attaches to the vascular endothelium, where it can promote further dissemination upon barrier penetration. Additionally, inhibition of C. albicans binding to endothelial cell αVβ3 using Cilengitide prevents endothelial dysfunction and therefore may present as a novel therapeutic approach for the treatment of fungal sepsis.
To cite this abstract in AMA style:Nader D, Curley G, Kerrigan S. Candida albicans Expresses an Integrin-like Protein that Promotes Endothelial Attachment and Vascular Leakage during Fungal Sepsis [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/candida-albicans-expresses-an-integrin-like-protein-that-promotes-endothelial-attachment-and-vascular-leakage-during-fungal-sepsis/. Accessed January 24, 2022.
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