title: Potent inhibition of neutrophil migration by cryptococcal mannoprotein-4-induced desensitization.
abstract: Cryptococcal capsular Ags induce the production of proinflammatory cytokines in patients with cryptococcal meningitis. Despite this, their cerebrospinal fluid typically contains few neutrophils. Capsular glucuronoxylomannan is generally considered to mediate the inhibition of neutrophil extravasation. In the current study, culture supernatant harvested from the nonglucuronoxylomannan-producing strain CAP67 was found to be as potent as supernatant from wild-type strains in preventing migration. We identified capsular mannoprotein (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, as suggested by its direct chemotactic activity. Supporting this hypothesis, MP-4 elicited Ca(2+) transients that were inhibited by preincubation with either 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 increased. Finally, MP-4 was clearly detectable in both serum and cerebrospinal fluid of patients suffering from cryptococcal meningitis. These findings identify MP-4 as a novel capsular Ag prematurely activating neutrophils and desensitizing them toward a chemoattractant challenge.
authors.affiliation: Division Infectious Diseases and AIDS, Department of Medicine, University Medical Center, 3508 GA Utrecht, The Netherlands. f.e.j.coenjaerts@lab.azu.nl
authors.forename: F E
authors.initials: FE
authors.lastname: Coenjaerts
authors.forename: A M
authors.initials: AM
authors.lastname: Walenkamp
authors.forename: P N
authors.initials: PN
authors.lastname: Mwinzi
authors.forename: J
authors.initials: J
authors.lastname: Scharringa
authors.forename: H A
authors.initials: HA
authors.lastname: Dekker
authors.forename: J A
authors.initials: JA
authors.lastname: van Strijp
authors.forename: R
authors.initials: R
authors.lastname: Cherniak
authors.forename: A I
authors.initials: AI
authors.lastname: Hoepelman
mesh_terms: D000942:Antigens, Bacterial / Q000097:blood / Q000494:pharmacology*; D018821:CD18 Antigens / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002630:Chemotactic Factors / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D003453:Cryptococcosis / Q000097:blood; D003454:Cryptococcus / Q000276:immunology / Q000472:pathogenicity*; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D006801:Humans; D019041:L-Selectin / Q000378:metabolism; D016177:Macrophage-1 Antigen / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000097:blood / Q000494:pharmacology*; D016920:Meningitis, Bacterial / Q000097:blood; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology; D011971:Receptors, Immunologic / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism
chemical_list: D000942:Antigens, Bacterial; D018821:CD18 Antigens; D002630:Chemotactic Factors; D016177:Macrophage-1 Antigen; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; D018124:Receptors, Tumor Necrosis Factor; C025363:mannoproteins; D019041:L-Selectin; D002118:Calcium