Abstract
C. albicans is a commensal yeast of the mucous membranes in healthy humans that can also cause disseminated candidiasis, mainly originating from the digestive tract, in vulnerable patients. It is necessary to understand the cellular and molecular mechanisms of the interaction of C. albicans with enterocytes to better understand the basis of commensalism and pathogenicity of the yeast and to improve the management of disseminated candidiasis. In this study, we investigated the kinetics of tight junction (TJ) formation in parallel with the invasion of C. albicans into the Caco-2 intestinal cell line. Using invasiveness assays on Caco-2 cells displaying pharmacologically altered TJ (i.e. differentiated epithelial cells treated with EGTA or patulin), we were able to demonstrate that TJ protect enterocytes against invasion of C. albicans. Moreover, treatment with a pharmacological inhibitor of endocytosis decreased invasion of the fungus into Caco-2 cells displaying altered TJ, suggesting that facilitating access of the yeast to the basolateral side of intestinal cells promotes endocytosis of C. albicans in its hyphal form. These data were supported by SEM observations of differentiated Caco-2 cells displaying altered TJ, which highlighted membrane protrusions engulfing C. albicans hyphae. We furthermore demonstrated that Als3, a hypha-specific C. albicans invasin, facilitates internalization of the fungus by active penetration and induced endocytosis by differentiated Caco-2 cells displaying altered TJ. However, our observations failed to demonstrate binding of Als3 to E-cadherin as the trigger mechanism of endocytosis of C. albicans into differentiated Caco-2 cells displaying altered TJ.
Highlights
Candida albicans is a dimorphic yeast and is the most frequently isolated yeast in humans
We demonstrated that endocytosis of C. albicans was a possible mechanism for the internalization of the yeast into intestinal epithelial cells (IEC) displaying altered tight junction (TJ)
Dalle et al previously reported that epithelial oral cells of the TR146 cell line were able to internalize C. albicans through an endocytic processes involving a zipper-like mechanism and a macropinocytosis-like process since endocytosis of C. albicans was drastically inhibited by cytochalasin D 0.5 M and amiloride 0.5 mM [8]
Summary
Candida albicans is a dimorphic yeast and is the most frequently isolated yeast in humans. Epithelial cells of the oral cavity and respiratory, urinary, and digestive tracts form an interface between a pathogen-rich lumen and an underlying basal zone of immune cells They are a major target for invasive micro-organisms, including fungi, as well as a site of intense host defences. Intestinal epithelial cells (IEC) are composed of a monolayer of differentiated and polarized enterocytes which display an apical side composed of microvilli which form the brush border that is exposed to the digestive lumen This monolayer of enterocytes ensures the integrity and impermeability of the intestinal barrier thanks to a complex hierarchical system of intercellular junctions including weak junctions (i.e. Adherens and Gap junctions, Desmosomes) and Tight Junctions (TJ), which are the most apically located intercellular junctions. We were not able to demonstrate the role of E-cadherin in this phenomenon
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