Adhesion of Candida albicans to Endothelial Cells under Physiological Conditions of Flow

Abstract

Candida albicans is a commensal organism that under certain circumstances can become pathogenic. During systemic infection C. albicans is disseminated via the circulation to distant organs, where it causes multiple organ failure. Despite the severity of systemic C. albicans infection, little is known about the mechanisms involved in the adhesion of this organism to the endothelium lining blood vessels. Previous studies have used static assays to examine adhesion. However, these do not realistically model blood vessels, where circulating C. albicans cells must adhere to the endothelium under conditions of flow and shear stress. Furthermore, there is conflicting evidence concerning the role played by yeast, pseudohyphal, and hyphal forms of C. albicans in adhesion to endothelium. To test the hypothesis that there may be differences in the abilities of these three morphogenic forms of C. albicans to adhere to endothelium under conditions of flow, we developed an in vitro flow adhesion assay. We found that all three forms of C. albicans rapidly bound to confluent endothelial cells under conditions of flow. Maximum adhesion was found at low shear stress levels similar to that found in postcapillary venules. Moreover, yeast forms bound in significantly greater numbers than did pseudohyphal and hyphal forms, respectively, contrasting with previous findings from static assays. These findings are consistent with recent in vivo data suggesting that yeast forms may be capable of adhering to the endothelium and migrating into the tissues before undergoing morphogenic change to cause tissue damage.

Hgc1 Mediates Dynamic Candida albicans-Endothelium Adhesion Events during Circulation

“…In our model, inoculated yeast cells always adhered relatively poorly. This is in agreement with the results of Grubb et al (14), who found that yeast adhesion at pressures over 3 dynes/cm 2 was also low. Strikingly, we observed a dramatic increase in adhesion kinetics during the first hour of circulation.…”

“…Furthermore, we have used a pressure which is similar to that found in capillary networks, have quantified the orien-tation of fungal hyphae relative to flow, and have analyzed the importance of fungal viability, the role of serum factors, and the importance of hypha-associated genes by using mutants lacking regulators of morphogenesis. Similar to Grubb et al (14), we found that C. albicans yeast and hyphae can rapidly adhere under flow. However, we also found that an adaptation event associated with the yeast-to-hypha transition can greatly enhance C. albicans-endothelium adhesion during circulation.…”

“…examining fungus-endothelium interactions under conditions of physical pressure similar to those found in the human bloodstream. To our knowledge, only two previous reports on C. albicans-endothelium interactions have used pump systems to mimic blood pressure and flow (11,14). Grubb et al (14) employed a linear flow system whereby C. albicans cells are held in an input reservoir suspended in medium and perfused over an endothelial monolayer and nonadherent cells flow out as waste.…”

Candida albicansdimorphism as a therapeutic target

“…In addition, it has been shown that physical properties and an optimal length (neither too short nor too long) promote endothelial adhesion during flow conditions, similar to the conditions in the bloodstream [50]. Differences in hyphal length may also explain why, in contrast to our results with germ tubes, Grubb et al found yeast cells adhered better than hyphae [51]. Furthermore, it should be noted that yeast cells dispersed from biofilms display increased adherence compared with their planktonic counterparts [22].…”

Human Endothelial Cells Internalize Candida parapsilosis via N-WASP-Mediated Endocytosis

“…C. albicans hyphae bind to endothelium much more efficiently than do yeast forms (12) in static adhesion assays. However, under conditions of fluid flow, which may be more appropriate to simulate actual adhesion in the bloodstream, C. albicans yeast forms bound more efficiently to endothelium (13). Several C. albicans adhesins have been identified, including the Als (agglutinin-like sequence) family (14)(15)(16).…”