The Cryptococcus neoformans capsule polysaccharide glucuronoxylomannan induces endothelial barrier permeability via the phosphorylation and internalization of VE‐cadherin

Abstract

Cryptococcus neoformans is a pathogenic yeast that has been shown to induce meningoencephalitis within immunocompromised individuals. This pathogen contributes to over 220,000 cases of fungal meningitis annually and is a major cause of mortality in patients with HIV in developing countries. C. neoformans sheds the polysaccharide glucuronoxylomannan (GXM) from its cell capsule, allowing the pathogen to evade the host immune systems and enter neuronal tissues. We hypothesize that C. neoformans GXM induces the disruption of the blood‐brain barrier by stimulating the breakdown of the adherens junctions that hold human brain endothelial cells together. Here, we demonstrate that GXM stimulates endothelial barrier permeability. We found that stimulation of human brain endothelial cells with GXM induces the internalization of VE‐cadherin from the plasma membrane, but not lysosomal sorting and degradation of VE‐cadherin. Instead, VE‐cadherin appears to be transiently phosphorylated and sorted to endosomes, suggesting that GXM‐mediated endothelial barrier disruption is reversible. Our current research is focused on identifying the intracellular signaling pathways that regulate VE‐cadherin phosphorylation and internalization in response to GXM exposure.Support or Funding InformationNIH NIAID: 1R01AI145559‐01A1