Effects of the capsular polysaccharides of Cryptococcus neoformans on phagocyte migration and inflammatory mediators

Abstract

An important virulence factor of the pathogenic fungus Cryptococcus neoformans is its polysaccharide capsule. The capsular polysaccharides glucuronoxylomannan (GXM), galactoxylomannan (GalXM) and the mannoproteins (MPs) display various immunomodulatory effects on the host response, such as the inhibition of phagocytosis, suppression of T-cell mediated immunity, and induction of immunogenic tolerance. Moreover, these capsular polysaccharides are able to interfere with the migration of phagocytes despite adequate stimulation of chemokine production and their concerted action accounts for the mild inflammatory response often observed in cryptococcosis. Different mechanisms contribute to this phenomenon. First, cryptococcal polysaccharides impair leukocyte migration towards chemoattractants. A combination of the intrinsic chemoattracting properties of circulating polysaccharides and the ability to induce cross-desensitization of chemokine receptors prevents leukocytes from leaving the bloodstream and migrating towards inflammatory site. Polysaccharide-induced repressive effects on the C5a receptor expression on neutrophils may also add to this impaired chemokinesis. Second, polysaccharides interfere with leukocyte adhesion to and migration through the endothelium. Both GXM and MP-4 induce L-selectin shedding from the surface of leukocytes; hence, interference with leukocyte rolling on the endothelium can be expected. GXM also interferes with the subsequent process of firm leukocyte adhesion to the endothelium in vitro. Thirdly, capsular polysaccharides enhance the production of anti-inflammatory interleukin-10 (IL-10) and induce tumor necrosis factor-alpha (TNFalpha) receptor loss from the surface of neutrophils. The capacity to reduce neutrophil influx makes cryptococcal polysaccharides interesting compounds to study in clinical models of inflammation (i.e.; sepsis, auto-immune disorders) in which leukocyte influx can be potentially damaging to host tissues.