title: Metabolites released by Cryptococcus neoformans var. neoformans and var. gattii differentially affect human neutrophil function.
abstract: Differences in the ability of Cryptococcus neoformans var. neoformans (CNVN) and var. gattii (CNVG) to establish localized lesions in the lungs of healthy humans remain unexplained. In this study, CNVG infection in a rat model was characterized by early neutrophil invasion into lung tissue, but phagocytosis of cryptococci was not observed. The chemical composition of non-enzymic components secreted by one strain of each variety (heat-inactivated supernatants from CNVN and CNVG, termed vns and vgs, respectively) were compared, using magnetic resonance spectroscopy. Effects on human neutrophil viability and functions at both pH 5.5 and 7.0 were investigated, as the pH of cryptococcomas was found to be 5.4-5.6 in vivo. The supernatants were similar in composition, although metabolites in vns were generally present in higher concentrations. In addition, vgs contained two novel metabolites-acetoin and dihydroxyacetone. Polyphosphate was observed in cells from both varieties and may be a source of extracellular inorganic phosphate. Superoxide production in the presence of phorbol ester was enhanced by treatment with vns and decreased by vgs. At pH 5.5, vns caused high levels of necrosis in neutrophils, as well as increased adhesion/migration through A549 lung epithelial cell monolayers. Individual supernatant components such as polyols, acetoin, dihydroxyacetone, and gamma-aminobutyric acid exhibited both pro- and anti-inflammatory properties. Overall, we found that vgs was potentially less pro-inflammatory than vns. Inhibition of neutrophil function by products of CNVG may promote survival of extracellular organisms, and local multiplication to form cryptococcomas.
authors.affiliation: Department of Infectious Diseases, Center for Infectious Diseases and Microbiology, Level 3, ICPMR Building, University of Sydney, Westmead Hospital, Westmead, NSW 2145, Australia. lesleyw@icpmr.wsahs.nsw.gov.au
authors.forename: Lesley
authors.initials: L
authors.lastname: Wright
authors.forename: William
authors.initials: W
authors.lastname: Bubb
authors.forename: John
authors.initials: J
authors.lastname: Davidson
authors.forename: Rosemary
authors.initials: R
authors.lastname: Santangelo
authors.forename: Mark
authors.initials: M
authors.lastname: Krockenberger
authors.forename: Uwe
authors.initials: U
authors.lastname: Himmelreich
authors.forename: Tania
authors.initials: T
authors.lastname: Sorrell
mesh_terms: D000818:Animals; D000946:Antigens, Fungal / Q000032:analysis; D001685:Biological Factors / Q000494:pharmacology; D002448:Cell Adhesion; D002465:Cell Movement; D003453:Cryptococcosis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D003455:Cryptococcus neoformans / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008172:Lung Diseases, Fungal / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D010710:Phosphates / Q000032:analysis; D051381:Rats; D011916:Rats, Inbred F344; D013481:Superoxides / Q000032:analysis; D013997:Time Factors
chemical_list: D000946:Antigens, Fungal; D001685:Biological Factors; D010710:Phosphates; D013481:Superoxides