Capsular polysaccharides from Cryptococcus neoformans modulate production of neutrophil extracellular traps (NETs) by human neutrophils (original) (raw)
In the present study, we characterized the in vitro modulation of NETs (neutrophil extracellular traps) induced in human neutrophils by the opportunistic fungus Cryptococcus neoformans, evaluating the participation of capsular polysaccharides glucuronoxylomanan (GXM) and glucuronoxylomannogalactan (GXMGal) in this phenomenon. The mutant acapsular strain CAP67 and the capsular polysaccharide GXMGal induced NET production. In contrast, the wild-type strain and the major polysaccharide GXM did not induce NET release. In addition, C. neoformans and the capsular polysaccharide GXM inhibited PMA-induced NET release. Additionally, we observed that the NET-enriched supernatants induced through CAP67 yeasts showed fungicidal activity on the capsular strain, and neutrophil elastase, myeloperoxidase, collagenase and histones were the key components for the induction of NET fungicidal activity. The signaling pathways associated with NET induction through the CAP67 strain were dependent on reactive oxygen species (ROS) and peptidylarginine deiminase-4 (PAD-4). Neither polysaccharide induced ROS production however both molecules blocked the production of ROS through PMA-activated neutrophils. Taken together, the results demonstrate that C. neoformans and the capsular component GXM inhibit the production of NETs in human neutrophils. This mechanism indicates a potentially new and important modulation factor for this fungal pathogen. C . neoformans is an opportunistic fungal pathogen of global distribution, which grows predominantly in the form of yeast and has a polysaccharide capsule that differentiates this microorganism from other pathogenic fungi. Cryptococcosis is prevalent in individuals with T cell deficiencies, such as those infected with HIV 1 . The capsular polysaccharide is the most well-studied structure of C. neoformans and is considered a major virulence factor 2 . In a murine experimental model, acapsular mutants are either incapable of inducing cryptococcosis or exhibit reduced virulence 3,4 . Biochemical studies have shown that the C. neoformans capsule primarily comprises glucuronoxylomannan (GXM), representing approximately 88% of the capsule. GXM is a polymer that consists mostly of a linear a-(1-3)-mannan substituted with b-(1-2)glucopyranosyluronic acid and b-(1-4)-xylopyranosyl. O-acetylation occurs on the C-6 of about half of the mannose residues 5,6 .
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