N-cadherin mediates endocytosis of Candida albicans by endothelial cells.
ABSTRACT Candida albicans is the most common cause of fungal bloodstream infections. To invade the deep tissues, blood-borne organisms must cross the endothelial cell lining of the vasculature. We have found previously that C. albicans hyphae, but not blastospores, invade endothelial cells in vitro by inducing their own endocytosis. Therefore, we set out to identify the endothelial cell receptor that mediates the endocytosis of C. albicans. We determined that endocytosis of C. albicans was not mediated by bridging molecules in the serum and that it was partially dependent on the presence of extracellular calcium. Using an affinity purification procedure, we discovered that endothelial cell N-cadherin bound to C. albicans hyphae but not blastospores. N-cadherin also co-localized with C. albicans hyphae that were being endocytosed by endothelial cells. Chinese hamster ovary (CHO) cells expressing human N-cadherin endocytosed significantly more C. albicans hyphae than did CHO cells expressing either human VE-cadherin or no human cadherins. The expression of N-cadherin by the CHO cells resulted in enhanced endocytosis of hyphae, but not blastospores, indicating the selectivity of the N-cadherin-mediated endocytosis. Down-regulation of endothelial cell N-cadherin expression with small interfering RNA significantly inhibited the endocytosis of C. albicans hyphae. Therefore, a novel function of N-cadherin is that it serves as an endothelial cell receptor, which mediates the endocytosis of C. albicans.
- SourceAvailable from: Scott G FillerVirulence 01/2014; 5(2). · 3.32 Impact Factor
Article: Fungal invasion of epithelial cells[Show abstract] [Hide abstract]
ABSTRACT: Interaction between host cells and invasive Candida plays a large role in the pathogenicity of Candida species. Fungal-induced endocytosis and active penetration are the two distinct, yet complementary invasion mechanisms of invasive candidiasis. Induced endocytosis is a microorganism-triggered, epithelial-driven, clathrin-mediated and actin-dependent process. During the fundamental pathological process of induced endocytosis, invasins (Als3 and Ssa1), which mediate the binding of host epithelial surface proteins, are expressed by Candida species on the hyphal surface. Sequentially, the interaction between invasins and host epithelial surface proteins stimulates the recruitment of clathrin, dynamin and cortactin to the sites where Candida enters epithelial cells, which in turn induce the actin cytoskeleton reorganization. Actin cytoskeleton provides the force required for fungal internalization. Parallely, active penetration of Candida can directly pass through epithelial cells possibly due to progressive elongation of hyphae and physical forces. Several molecules, such as secreted hydrolases and Als3, can affect the protective barrier of the epithelium and make Candida actively penetrate into epithelial cells through intercellular gaps of epithelial layers.Microbiological Research 11/2014; · 1.94 Impact Factor
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ABSTRACT: Oral candidiasis remains one of the most common forms of Candida infections and occurs if the balance between host, Candida and microbiota is disturbed, e.g., by broad spectrum antibiotics or immunosuppression. In recent years, identification of fungal factors contributing to host cell damage and new insights into host defense mechanisms have significantly extended our understanding of the pathogenesis of oral candidiasis. In this review, we will provide an overview of the pathogenicity mechanisms during oral Candida infections and discuss some approaches by which this knowledge could be transferred into therapeutic approaches.Expert Review of Anticancer Therapy 05/2014; · 3.22 Impact Factor