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Macrophage Cholesterol Depletion and Its Effect on the Phagocytosis of Cryptococcus neoformans
Published on: December 19, 2014
Potent inhibition of neutrophil migration by cryptococcal mannoprotein-4-induced desensitization
F E Coenjaerts1, A M Walenkamp, P N Mwinzi
1Division Infectious Diseases and AIDS, Department of Medicine, University Medical Center, 3508 GA Utrecht, The Netherlands. f.e.j.coenjaerts@lab.azu.nl
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.
Insights
Cryptococcal mannoprotein (MP)-4, a novel capsular antigen, prematurely activates neutrophils. This desensitizes them to chemoattractants, explaining low neutrophil counts in cryptococcal meningitis.
Area of Science:
- Immunology
- Microbiology
- Infectious Diseases
Background:
- Cryptococcal capsular antigens (Ags) trigger proinflammatory cytokines in cryptococcal meningitis.
- Despite inflammation, cerebrospinal fluid (CSF) in these patients typically shows low neutrophil counts.
- Capsular glucuronoxylomannan is hypothesized to inhibit neutrophil extravasation.
Purpose of the Study:
- To identify the specific cryptococcal capsular antigen responsible for inhibiting neutrophil migration.
- To elucidate the mechanism by which this antigen affects neutrophil function.
- To determine the presence of this antigen in patient serum and CSF.
Main Methods:
- Compared the effect of culture supernatant from wild-type and glucuronoxylomannan-deficient cryptococcal strains on neutrophil migration.
- Purified and tested the inhibitory effect of capsular mannoprotein (MP)-4 on neutrophil migration towards various chemoattractants.
- Investigated MP-4's mechanism of action using calcium (Ca2+) imaging and assessed changes in neutrophil surface receptor expression (L-selectin, TNF receptors, CD11b/18).
- Detected MP-4 in serum and CSF from patients with cryptococcal meningitis.
Main Results:
- Culture supernatant from a nonglucuronoxylomannan-producing strain inhibited neutrophil migration similarly to wild-type strains.
- Purified capsular mannoprotein (MP)-4 inhibited neutrophil migration towards platelet-activating factor, IL-8, and fMLP.
- MP-4 demonstrated chemotactic activity, suggesting chemoattractant receptor cross-desensitization.
- MP-4 induced Ca2+ transients, decreased L-selectin, and increased CD11b/18 expression, while shedding TNF receptors.
- MP-4 was detected in the serum and CSF of patients with cryptococcal meningitis.
Conclusions:
- Capsular mannoprotein (MP)-4 is identified as a novel cryptococcal antigen.
- MP-4 prematurely activates neutrophils, leading to desensitization towards chemoattractant challenges.
- This mechanism likely contributes to the low neutrophil counts observed in the CSF of cryptococcal meningitis patients.
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