Cryptococcal glucuronoxylomannan interferes with neutrophil rolling on the endothelium

Abstract

The major capsular polysaccharide glucuronoxylomannan (GXM) of the pathogenic fungus Cryptococcus neoformans has been associated with depression of a variety of immunological host responses. For one, GXM has been shown to interfere with the migration of phagocytes to sites of inflammation by interference with both chemokinesis and leucocyte adhesion to the endothelium. We reported previously that GXM blocks the firm adhesion of neutrophils (PMNs) to endothelium in a static adhesion model, most probably by interfering with E-selectin binding pathways. Using a flow model, we now demonstrate that GXM also interferes with the initial rolling phase of PMN adhesion to endothelium (40% decrease) as well as to E-selectin-transfected CHO cells (43% inhibition). Furthermore, we show that CD14 and TLR4, which are known receptors for GXM, mediate this interference with PMN rolling. However, thus far, we are not able to identify the ligand of E-selectin on the surface of PMNs that is specifically affected by GXM. In conclusion, cryptococcal GXM interferes with both rolling and fixed binding of neutrophils on the endothelium, providing a novel means of contributing to the absence of neutrophil infiltration observed in cryptococcal infections.