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PubMed2007

The iron- and cAMP-regulated gene SIT1 influences ferrioxamine B utilization, melanization and cell wall structure in Cryptococcus neoformans.

The mechanisms by which pathogens sense and transport iron are important during infection, because of the low availability of free iron in the mammalian host. Iron is a key nutritional cue for the pathogen Cryptococcus neoformans, because it influences expression of the polysaccharide capsule that is the major virulence factor of the fungus. In this study, C. neoformans mutants were constructed with a defect in the iron-regulated gene SIT1 that encodes a putative siderophore iron transporter. Analysis of mutants in serotype A and D strains demonstrated that SIT1 is required for the use of siderophore-bound iron, and for growth in a low-iron environment. The sit1 mutants also showed changes in melanin formation and cell wall density, and it was found that mutants defective in protein kinase A, which is known to influence melanization and capsule formation, showed elevated SIT1 transcripts in both the serotype A and the serotype D backgrounds. Finally, the mutants were tested for virulence in a murine model of cryptococcosis, and it was found that SIT1 was not required for virulence. Overall, these studies establish links between iron acquisition, melanin formation and cAMP signalling in C. neoformans.

Animals↗
PubMed1997

Influence of different conditions on kinetics of tumor necrosis factor alpha release by peripheral blood mononuclear cells after stimulation with Cryptococcus neoformans: a possible explanation for different results.

In available literature, different kinetics for tumor necrosis factor alpha (TNF-alpha) release by peripheral blood mononuclear cells are reported upon stimulation with Cryptococcus neoformans. Results in this study showed that shaking cells gives faster kinetics of TNF-alpha release while large working volumes give lower TNF-alpha concentrations. Different experimental conditions thus influence kinetics of TNF-alpha release by phagocytes.

Cryptococcus neoformans↗
PubMed1999

Differential effect of Cryptococcus neoformans on the production of IL-12p40 and IL-10 by murine macrophages stimulated with lipopolysaccharide and gamma interferon.

In the present study, we examined the in vitro effect of Cryptococcus neoformans on the production of interleukin-12 (IL-12) and IL-10 by murine macrophages. At a dose of 1 x 10(5), 1 x 10(6) or 1 x 10(7) ml-1, a highly virulent strain of C. neoformans (strain YC-11) suppressed the production of IL-12p40 by a murine macrophage cell line, J774.1 stimulated with lipopolysaccharide (LPS) and interferon (IFN)-gamma, while the production of IL-10 was not inhibited, but rather slightly augmented. The suppression of IL-12p40 production did not change by neutralizing anti-IL-10 mAb. A direct contact of C. neoformans with macrophages was largely involved in this inhibitory effect, since placement of a 0.45 micron pore membrane between the organism and macrophages prevented such effect. On the other hand, the culture supernatant of YC-11 did not inhibit macrophage IL-12p40 production when used at a lower dose, which contained an equivalent amount of capsular polysaccharide to that in the supernatant of YC-11 cultured at 1 x 10(5) or 1 x 10(6) ml-1, although it showed a small suppression at higher doses. Our results suggest that C. neoformans may suppress the induction of Th1 responses by inhibiting macrophage IL-12 production predominantly through a direct contact-dependent mechanism and to a lesser extent by a certain soluble factor(s) released from this microorganism.

Animals↗
PubMed2001

Encephalomyelitis due to Cryptococcus neoformans var gattii presenting as spinal tumour: case report and review of the literature.

A 24 year old immunocompetent German resident is described who developed multifocal encephalomyelitis due to infection with Cryptococcus neoformans var gatti, commonly considered a disease of tropical regions. In the light of current knowledge on the epidemiology of C neoformans var gatti and the travel history of the patient it is assumed that the infection was acquired outside Europe. As exclusive intramedullary involvement is an outstandingly rare manifestation in spinal cryptococcosis, the particular diagnostic procedure and the therapeutic strategies are discussed

Adult↗
PubMed2006

Cryptococcus neoformans glycoantigens are captured by multiple lectin receptors and presented by dendritic cells.

Cell-mediated immune responses to glycoantigens have been largely uncharacterized. Protective T cell responses to the pathogenic yeast Cryptococcus neoformans are dependent on heavily mannosylated Ags termed mannoproteins. In the work presented, the innate immune response to mannoprotein was determined. Purified murine splenic dendritic cells (DC), B cells, and macrophages were used to stimulate mannoprotein-specific T cells. Only DC were capable of any measurable stimulation. Depletion of DC resulted in the abrogation of the T cell response. Human and murine DC rapidly captured fluorescent-labeled mannoprotein by a mannose receptor-mediated process. Using transfected cell lines, the type II C-type lectin receptor DC-specific ICAM-3-grabbing nonintegrin (CD209) was determined to have affinity for mannoprotein. Taken together with prior work demonstrating that mannoprotein was captured by the macrophage mannose receptor (CD206), these data suggest that multiple mannose receptors on DC recognize mannoprotein. Pulsing experiments demonstrated that DC captured sufficient mannoprotein over 2 h to account for 50% of total stimulation. Capture appeared dependent on mannose receptors, as competitive mannosylated inhibitors and calcium chelators each interfered with T cell stimulation. By confocal microscopy, intracellular mannoprotein trafficked to an endo-lysosomal compartment in DC, and at later time points extended into tubules in a similar fashion to the degradation marker DQ-OVA. Mannoprotein colocalized intracellularly with CD206 and CD209. These data suggest that DC provide the crucial link between innate and adaptive immune responses to C. neoformans via a process that is dependent upon the efficient uptake of mannoprotein by mannose receptors.

Animals↗
PubMed1993

Evaluation of commercially available acridinium ester-labeled chemiluminescent DNA probes for culture identification of Blastomyces dermatitidis, Coccidioides immitis, Cryptococcus neoformans, and Histoplasma capsulatum.

Four commercially available acridinium ester-labeled DNA probes directed against rRNA were evaluated for their ability to identify Blastomyces dermatitidis, Coccidioides immitis, Histoplasma capsulatum, and Cryptococcus neoformans in culture. rRNA was extracted by sonication of 1- to 2-mm2 portions of cultures of fungi in two chaotropic reagents with glass beads. Following a heat inactivation step, the extracts were hybridized in solution with probes specific for each pathogen. The acridinium ester reporter moiety of nonhybridized probe was selectively hydrolyzed, and chemiluminescence of specific DNA:RNA hybrids was quantitated in relative light units with a luminometer. A positive identification required a relative light unit value of > or = 50,000. Sensitivity and specificity of the probes were determined by probing cultures of the respective pathogenic fungi (target) and nontarget fungi. Both mycelial and yeast forms of the dimorphic fungi (B. dermatitidis and H. capsulatum) were tested. For B. dermatitidis, sensitivity and specificity were 87.8 and 100%, respectively (74 target and 219 nontarget fungi tested). For C. immitis, sensitivity and specificity were 99.2 and 100%, respectively (122 target and 164 nontarget fungi tested). For H. capsulatum, sensitivity and specificity were 100 and 100%, respectively (86 target and 154 nontarget fungi tested). For C. neoformans, sensitivity and specificity were 97 and 100%, respectively (100 target and 230 nontarget fungi tested). For B. dermatitidis, C. immitis, and C. neoformans, repeat testing increased the respective sensitivities to 97.3, 100, and 100%. The high sensitivities and specificities of the probes, the relatively short time (less than 1 h) required to perform the assay, and the availability of standardized reagent kits make the acridinium ester-labeled DNA probes well suited to laboratories in need of a rapid method to identify these fungal pathogens. Further, use of the probes to identify pathogenic fungi as soon as colonies appear on primary recovery media significantly shortens the time to reporting.

Acridines↗
PubMed2000

Melanisation of Cryptococcus neoformans in human brain tissue.

Melanin-specific reagents revealed melanin in cryptococcal cell walls from human brain tissue, and fungal-cell melanin "ghosts" were recovered from infected tissue. The results indicate that Cryptococcus neoformans melanises during human infection.

Amphotericin B↗
PubMed2006

Cryptococcus neoformans strains isolated from church towers in Rio de Janeiro City, RJ, Brazil.

Cryptococcosis has been a significant cause of morbidity and mortality in patients with Aids. Many reservoirs of the agent Cryptococcus neoformans have been reported, but the ecology of this yeast must be elucidated in order to establish surveillance programs and to prevent infections. The objective of this study was to evaluate the presence of C. neoformans in Rio de Janeiro City, RJ, Brazil. Ten churches were selected for sampling and detection of the yeast collecting pigeon dropping, air samples from church towers and neighboring areas during one year. The data demonstrated that C. neoformans has been present in every church selected and was present in 37.8% of 219 pigeon dropping samples. As well as, the yeast was isolated from soil, insects, eggs, pigeon nests and feathers. Fifteen air samples (4.9%) were positive. The growth on C.G.B. medium showed that all strains belonged to C. neoformans var. neoformans, with 98.8% of the strains belonging to serotype A.

Animals↗
PubMed1989

Staib agar supplemented with a triple antibiotic combination for the detection of Cryptococcus neoformans in clinical specimens.

It was demonstrated that the in vitro growth of a mucoid Escherichia coli strain from the urine of an AIDS patient could disturb the concurrent growth of Cryptococcus neoformans and the development of its brown colour effect (BCE) on Staib agar (syn. Guizotia abyssinica creatinine agar, bird seed agar, niger seed agar etc.) supplemented with penicillin + streptomycin. Owing to the supplementation with the triple antibiotic combination of penicillin + streptomycin + gentamicin and the resulting inhibition of E. coli growth, the formation of an intense BCE of the Cr. neoformans colonies after 3 d at 26 degrees C could be observed. On the same medium supplemented with this triple antibiotic combination 40 Cr. neoformans strains tested showed growth with an intense BCE after 3 d at 26 degrees C; but on Emmons' neutral Sabouraud's dextrose agar (NSDA) supplemented with the same triple antibiotic combination, inhibition of growth was found. For the examination of clinical specimens for Cr. neoformans contaminated with gram-negative rod-like bacteria, Staib agar supplemented with this triple antibiotic combination is proposed. Various antibiotic supplements to primary recovery media for fungi are discussed and ecological interrelations of bacteria and fungi are emphasized.

Acquired Immunodeficiency Syndrome↗
PubMed1987

Colonization and pathogenesis of Cryptococcus neoformans in gnotobiotic mice.

Congenitally immunodeficient nude (nu/nu) mice and their immunocompetent littermates (nu/+) were used to determine whether the absence of thymus-matured T cells would alter the capacity of Cryptococcus neoformans to colonize their mucosal surfaces or enhance their susceptibility to systemic cryptococcosis, or both, following oral challenge. We present data demonstrating that an encapsulated strain of C. neoformans serotype A colonized the alimentary tracts of germfree, conventional, and antibiotic-treated conventional nu/nu mice. Scanning electron microscopy showed that C. neoformans adhered to the epithelial surfaces of the oral cavities, esophagi, and gastrointestinal tracts of monoassociated nu/nu and nu/+ mice, and culture data showed that there were more viable C. neoformans cells in the alimentary tracts of nu/nu mice than of nu/+ mice. Tetracycline-treated conventional nu/nu, but not nu/+, mice were also colonized with C. neoformans following intragastric challenge. C. neoformans-monoassociated and tetracycline-treated conventional nu/nu mice succumbed to disseminated cryptococcosis with cerebral involvement 3 to 4 weeks after oral challenge, whereas no mortality was observed for similarily challenged nu/+ mice. These results demonstrate that an encapsulated strain of C. neoformans can colonize mucosal surfaces and cause systemic cryptococcosis in immunodeficient nu/nu mice, suggesting that the alimentary tract can be a portal of entry for C. neoformans in an immunodeficient host. These data also indicate that functional T cells play an important role in resistance to systemic cryptococcosis of endogenous origin.

Animals↗
PubMed1986

Activation of the complement system by Cryptococcus neoformans leads to binding of iC3b to the yeast.

The complement system plays a key role in resistance to cryptococcosis. In the present study, we examined several factors that influence the binding of C3 cleavage fragments to Cryptococcus neoformans. Binding of C3 was determined by using normal human serum supplemented with 125I-labeled C3. Incubation of encapsulated cryptococci in 20% serum led to the binding of approximately 3.2 X 10(6) molecules of C3 to each cell. The binding of C3 was markedly inhibited by heating the serum at 56 degrees C for 30 min or by chelation of the serum with EDTA. Chelation of the serum with EGTA [ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid] reduced binding of C3 by 37%. These results indicated that activation of C3 cleavage fragments and their binding to C. neoformans was primarily dependent upon the alternative pathway. Bound C3 could be removed by incubation with 1.0 M hydroxylamine (pH 10) but not by incubation with 3.5 M NaSCN or with phosphate-buffered saline containing 0.1% sodium dodecyl sulfate. These results suggested that C3 fragments were bound to C. neoformans by ester bonds. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of C3 fragments eluted from the yeast showed the presence of protein bands consistent with the presence of iC3b. C3b was not detected on the yeast after incubation with serum for time intervals as short as 2.5 min, indicating a rapid conversion of cell-bound C3b to iC3b. These results indicate that iC3b is the ligand which most likely interacts with the phagocyte C3 receptors involved in the phagocytosis of C. neoformans.

Complement Activation↗
PubMed2000

Immunosuppressive and nonimmunosuppressive cyclosporine analogs are toxic to the opportunistic fungal pathogen Cryptococcus neoformans via cyclophilin-dependent inhibition of calcineurin.

Cyclosporine (CsA) is an immunosuppressive and antimicrobial drug which, in complex with cyclophilin A, inhibits the protein phosphatase calcineurin. We recently found that Cryptococcus neoformans growth is resistant to CsA at 24 degrees C but sensitive at 37 degrees C and that calcineurin is required for growth at 37 degrees C and pathogenicity. Here CsA analogs were screened for toxicity against C. neoformans in vitro. In most cases, antifungal activity was correlated with cyclophilin A binding in vitro and inhibition of the mixed-lymphocyte reaction and interleukin 2 production in cell culture. Two unusual nonimmunosuppressive CsA derivatives, (gamma-OH) MeLeu(4)-Cs (211-810) and D-Sar (alpha-SMe)(3) Val(2)-DH-Cs (209-825), which are also toxic to C. neoformans were identified. These CsA analogs inhibit C. neoformans via fungal cyclophilin A and calcineurin homologs. Our findings identify calcineurin as a novel antifungal drug target and suggest nonimmunosuppressive CsA analogs warrant investigation as antifungal agents.

Animals↗
PubMed2004

Isolation of Cryptococcus neoformans in Antwerp Zoo's nocturnal house.

Cryptococcosis was diagnosed postmortem in a striped grass mouse (Lemniscomys barbarus) housed in the nocturnal department of Antwerp Zoo. Eight of the remaining mice in the cage were captured. Cryptococcus neoformans was isolated from the lung of one animal. Two mice had an elevated serum cryptococcal antigen titre. On examination of the pooled faecal samples collected from 17 animal species housed in 23 cages of the nocturnal department, the pathogenic yeast was isolated from the faeces of the striped grass mice and a degu (Octodon degus). Numerous Cr. neoformans colonies were isolated from a tree-trunk, tree-stumps, and decaying wood collected from a hollow tree used to decorate the animals cage. Subsequent examination in four other cages of the nocturnal department revealed that all the sampled tree-trunks were colonized by Cr. neoformans. The fungus was isolated from the air sampled in the cage of the degu. Air samples collected in the public and service corridors remained negative. All the isolated strains were identified as Cr. neoformans var. neoformans serotype A.

Animals↗
PubMed2000

In vitro susceptibility studies of Cryptococcus neoformans isolated from patients with no clinical response to amphotericin B therapy.

The in vitro activities of three antifungal drugs alone and in combination were evaluated against five isolates of Cryptococcus neoformans using time-kill curves (TKC). The isolates were from AIDS patients who had either died or had failed to show a clinical response during amphotericin B (AMB) treatment. AMB, fluconazole (FCZ) and flucytosine (5FC), and combinations of the drugs (AMB plus 5FC, AMB plus rifampicin (RIF) and FCZ plus 5FC), were evaluated. With all five isolates AMB did not show fungicidal activity; instead, a persistent or tolerant effect was observed. Combinations of AMB plus 5FC and AMB plus RIF showed a clear synergic effect, except for one isolate tested with AMB plus RIF. In contrast, the FCZ plus 5FC combination did not inhibit growth of any isolate.

Acquired Immunodeficiency Syndrome↗
PubMed2004

Effects of several antifungal drug combinations against clinical and environmental isolates of Cryptococcus neoformans from China.

The in vitro interactions of caspofungin (CSP) with terbinafine (TRB) and ravuconazole (RVC) with 5-fluorocytosine (5-FC) were tested against 82 clinical and environmental isolates of Cryptococcus neoformans from China. The interaction of CSP with TRB proved synergistic against those isolates with a CSP MIC < or =2 microg ml-1 (5% of the isolates), additive against 42% of the isolates and indifferent against 53%. The effects of RVC with 5-FC were synergistic, additive or indifferent against 8%, 26% and 67% of the isolates, respectively. No antagonistic effects were found among any of the drugs. The combinations of CSP with TRB and RVC with 5-FC may display beneficial effects in a strain-dependent manner, while in no case showed antagonistic effects. These data might be of use to design safer and more efficient treatments for patients with cryptococcosis and warrant further evaluation.

Animals↗
PubMed1991

Glucuronoxylomannan of Cryptococcus neoformans serotype B: structural analysis by gas-liquid chromatography-mass spectrometry and 13C-nuclear magnetic resonance spectroscopy.

The major extracellular polysaccharide (glucuronoxylomannan, GXM) from six strains of Cryptococcus neoformans serotype B was characterized by gas-liquid chromatography (g.l.c.), g.l.c.-mass spectrometry (g.l.c.-m.s.), and nuclear magnetic resonance (n.m.r.) spectroscopy. Ultrasonic irradiation (u.i.) was used to reduce the mol.wt. of native GXM from 9.75 x 10(5) to 1.15 x 10(5) without apparent change in its composition (GXM-S). The Xylp:Manp:GlcpA molar ratio of the GXM and GXM-S from the six strains of C. neoformans serotype B is approximately 3.5:3.0:0.6. GXM-S was O-deacetylated (GXM-D) by treatment with NH4OH. The 13C-n.m.r. analysis of GXM-D gave spectra that served as characteristic fingerprints of the structure and also facilitated the assignment of the anomeric carbon resonances to specific structural moieties present in GXM-D. The GXM-D from each serotype B strain was found to be similar by 13C-n.m.r. spectroscopy. The structure contains a linear (1----3)-alpha-D-Manp backbone substituted with 2-O-beta-GlcpA and 2-O-beta-Xylp. beta-Xylp is also O-4 linked to the Manp substituted with GlcpA. In addition, a model for the disposition of the Xylp and GlcpA side chain substituents along the mannopyranan backbone is proposed, based upon results from the combination of g.l.c.-m.s. and 13C-n.m.r. spectroscopy.

Carbohydrate Sequence↗