Potent inhibition of neutrophil migration by cryptococcal mannoprotein-4-induced desensitization

Cryptococcal capsular Ags induce the production of proinflammatory cytokine s in patients with cryptococcal meningitis. Despite this, their cerebrospin al fluid typically contains few neutrophils. Capsular glucuronoxylomannan i s generally considered to mediate the inhibition of neutrophil extravasatio n. In the current study, culture supernatant harvested from the nonglucuron oxylomannan-producing strain CAP67 was found to be as potent as supernatant from wild-type strains in preventing migration. We identified capsular man noprotein (MP)-4 as the causative agent. Purified MP-4 inhibited migration of neutrophils toward platelet-activating factor, IL-8, and fMLP, probably via a mechanism involving chemoattractant receptor cross-desensitization, a s suggested by its direct chemotactic activity. Supporting this hypothesis, MP-4 elicited Ca2+ transients that were inhibited by preincubation with ei ther fMLP, IL-8, or C5a, but not platelet-activating factor, and vice versa . Moreover, MP-4 strongly decreased the neutrophil surface expression of L- selectin and induced shedding of TNF receptors p55/p75, whereas CD11b/18 in creased. Finally, MP-4 was clearly detectable in both serum and cerebrospin al fluid of patients suffering from cryptococcal meningitis. These findings identify MP-4 as a novel capsular Ag prematurely activating neutrophils an d desensitizing them toward a chemoattractant challenge.