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PubMed1981

Immediate hypersensitivity to Cryptococcus neoformans.

The role of the capsular polysaccharide in anaphylactic reactions to Cryptococcus neoformans was investigated. Groups of mice were sensitized with viable cells of either a moderately encapsulated strain of C. neoformans or a non-encapsulated variant. Anaphylactic reactions were observed in both groups of mice to a similar extent when challenged with whole cells. Mice sensitized with the encapsulated strain and challenged with homologous polysaccharide showed only mild hypersensitivity symptoms. Mice sensitized with either the encapsulated or the nonencapsulated strain showed cross-reactivity when challenged with killed cells of the heterologous strain. These data indicate that the capsular polysaccharide plays a minor role in anaphylactic reactions to C. neoformans and that the sensitizing antigen is probably located in the cell wall of the yeast.

Anaphylaxis↗
PubMed1982

In vitro interactions of immune lymphocytes and Cryptococcus neoformans.

CBA/J mice immunized subcutaneously with emulsions of heat-killed Cryptococcus neoformans in complete Freund adjuvant displayed delayed-type hypersensitivity to cryptococcal culture filtrate antigen and developed sensitized splenic lymphoid cells which inhibited the growth of C. neoformans in vitro. The in vitro assay of growth inhibition served to investigate further the kinetics of the effect of sensitized lymphoid cells on the pathogen. There was a close correlation between the delayed-type hypersensitivity response in mice and inhibition of growth of C. neoformans by lymphoid cells. Sensitized splenic lymphocytes capable of inhibiting the growth of the cryptococci were detected at day 6 after immunization and reached maximum levels by days 8 through 16. Inhibition of growth was highest with effector-to-target cell ratios of 300:1 or greater. Inhibition of growth of C. neoformans by sensitized lymphoid cells was detectable as early as 4 h after effector and target cells were mixed and increased gradually, reaching a maximum at 24 h, but dropped significantly by 48 h. By supplementing the reaction mixtures with fresh medium or additional sensitized effector cells during incubation, the inhibition of growth of C. neoformans could be maintained through 48 h. C. neoformans-sensitized effector lymphoid populations not only inhibited the growth of the pathogen in vitro but also restricted C. neoformans proliferation in various vital organs upon transfer to naive recipient animals, indicating that the in vitro growth inhibition assay may be a means of assessing the resistance of animals to C. neoformans. The effector cells from sensitized animals were nylon wool-nonadherent Thy-1+ and Ia+ lymphocytes.

Animals↗
PubMed1995

The Cryptococcus neoformans GAL7 gene and its use as an inducible promoter.

A Cryptococcus neoformans galactose auxotroph was created by ultraviolet light mutagenesis and complemented with a C. neoformans genomic library. The translated sequence of the complementing DNA revealed a high degree of similarity to a number of UDP glucose-D-galactose-1-phosphate uridylyltransferases. Expression of C. neoformans GAL7 mRNA followed a pattern similar to Saccharomyces cerevisiae expression; it was first observed within 2.5 min of induction and fully induced by 30 min. The gene was completely repressed in the presence of glucose. The GAL7 promoter was isolated and used to construct a promoter cassette. Two genes were tested in this cassette for galactose regulation by creating GAL7 promoter fusions with their coding regions. MF alpha, which encodes a pheromone, was found to produce filaments only in transformants that were induced by galactose. A second gene, beta-glucuronidase (gusA), which is a commonly used reporter gene, was tested and also found to be expressed. When the GAL7p::GUS fusion was used to quantify inducibility of the GAL7 promoter, the level of enzyme activity was at least 500-fold greater for cells grown in galactose than for cells grown in glucose. The GAL7 promoter is the first inducible promoter characterized in C. neoformans and the GUS gene is the first heterologous gene shown to be expressed in this yeast pathogen.

Amino Acid Sequence↗
PubMed2001

Melanization of Cryptococcus neoformans reduces its susceptibility to the antimicrobial effects of silver nitrate.

Cryptococcus neoformans is a human pathogenic fungus that is frequently found in avian feces and Eucalyptus trees. There is evidence that C. neoformans can make a melanin-like pigment in pigeon excreta, a major natural environmental niche. Silver nitrate, AgNO3, is a highly toxic compound for bacteria and fungi. In this study we investigated the effects of melanin production by C. neoformans on the susceptibility of this fungus to AgNO3. C. neoformans was grown in media with and without the melanin precursor, L-dopa, for various times and susceptibility to AgNO3 was determined by measuring percentage of survival after incubation in AgNO3. There was an inverse association between time allowed for melanization and susceptibility to Ag+. Addition of melanin particles to a suspension of non-melanized C. neoformans cells reduced their susceptibility to AgNO3, consistent with metal ion chelation by melanin. Binding of Ag+ to melanin particles was demonstrated by atomic absorption spectroscopy. The results indicate that melanization of C. neoformans reduces susceptibility to a toxic heavy metal. This suggests a role for melanin in environmental protection against heavy metal toxicity.

Anti-Bacterial Agents↗
PubMed1993

Effects of itraconazole on cytochrome P-450-dependent sterol 14 alpha-demethylation and reduction of 3-ketosteroids in Cryptococcus neoformans.

As in other pathogenic fungi, the major sterol synthesized by Cryptococcus neoformans var. neoformans is ergosterol. This yeast also shares with most pathogenic fungi a susceptibility of its cytochrome P-450-dependent ergosterol synthesis to nanomolar concentrations of itraconazole. Fifty percent inhibition of ergosterol synthesis was reached after 16 h of growth in the presence of 6.0 +/- 4.7 nM itraconazole, and complete inhibition was reached at approximately 100 nM itraconazole. This inhibition coincided with the accumulation of mainly eburicol and the 3-ketosteroid obtusifolione. The radioactivity incorporated from [14C]acetate in both compounds represents 64.2% +/- 12.9% of the radioactivity incorporated into the sterols plus squalene extracted from cells incubated in the presence of 10 nM itraconazole. The accumulation of obtusifolione as well as eburicol indicates that itraconazole inhibits not only the 14 alpha-demethylase but also (directly or indirectly) the NADPH-dependent 3-ketosteroid reductase, i.e., the enzyme catalyzing the last step in the demethylation at C-4. This latter inhibition obviates the synthesis of 4,4-demethylated 14 alpha-methylsterols that may function at least partly as surrogates of ergosterol. Eburicol and obtusifolione are unable to support cell growth, and the 3-ketosteroid has been shown to disturb membranes. The complete inhibition of ergosterol synthesis and the accumulation of the 4,4,14-trimethylsterol and of the 3-ketosteroid together with the absence of sterols, such as 14 alpha-methylfecosterol and lanosterol, which can partly fulfill some functions of ergosterol, are at the origin of the high activity of itraconazole against C. neoformans. Fifty percent inhibition of growth achieved after 16 h of incubation in the presence of 3.2 +/- 2.6 nM itraconazole.

Cryptococcus neoformans↗
PubMed1967

Cryptococcus neoformans. I. Nonencapsulated mutants.

Seven nonencapsulated mutants of Cryptococcus neoformans were isolated from an encapsulated strain of human origin. Initially, the mutants were avirulent for mice. After several months of subculturing, six of the seven isolates reverted to the encapsulated state and possessed varying degrees of virulence. The results of these experiments suggest that a strong correlation exists between the presence of a capsule and the virulence of C. neoformans.

Animals↗
PubMed1984

Epidemiologic differences between the two varieties of Cryptococcus neoformans.

This report of the worldwide distribution of two varieties of Cryptococcus neoformans was drawn from data on 628 clinical isolates and from data on 97 additional isolates from other laboratories. Tests showed that 100% of the cultures from Austria, Belgium, Denmark, France, Germany, Holland, Italy, Switzerland, and Japan belonged to C. neoformans var. neoformans. More than 85% of the isolates from Argentina, Canada, the United Kingdom, and the United States (except southern California) were of C. neoformans var. neoformans, the remainder being of C. neoformans var. gattii . There was an unusually high prevalence (35-100%) of C. neoformans var. gattii in Australia, Brazil, Cambodia, Hawaii, southern California, Mexico, Paraguay, Thailand, Vietnam, Nepal, and countries in central Africa. These findings indicated that C. neoformans var. gattii is prevalent only in tropical and subtropical regions. Seventy per cent of the total isolates studied were of serotype A of C. neoformans var. neoformans. Serotype D (9% of the total) was common in Europe, but was found infrequently in other regions. Among the two serotypes of C. neoformans var. gattii , serotype B was 4.5 times more prevalent than serotype C. The majority (88%) of type C isolates in our collection were from southern California.

Africa↗
PubMed1975

Pigment production by Cryptococcus neoformans from para- and ortho-Diphenols: effect of the nitrogen source.

Cryptococcus neoformans produced pigments when p-diphenols were substrates in a glucose-amino acid-salts medium. The best substrates were 2.5-dihydroxybenzoic acid and 2,5-dihydroxybenzenesulfonic acid. In contrast to the cellular pigment production from o-diphenols (hydroxyl groups in the 2,3- or 3,4-position of phenyl ring), the p-diphenols (1,4- or 2,5-positions for the hydroxyl groups) produced large amounts of soluble pigments that diffused into the medium. When an optimal source of nitrogen (glutamine, glycine, and asparagine) was used, 89% of the C. neoformans strains produced pigments from p-diphenols. In contrast, 0 to 67% of the strains produced pigments when a suboptimal nitrogen source (proline, ammonium sulfate, ornithine, and methionine) was used. When glutamine-glycine-asparagine was the nitrogen source, 100% of the C. neoformans strains produced pigments from o0diphenols, whereas 77 to 100% of the strains produced pigment when proline-ammonium sulfate-ornithine-methionine was the nitrogen source. Cryptococcus species other than C. neoformans and all tested Candida species failed to produce pigments from any of the substrates except when hydroquinone was used. A combination of glutamine-glycine-asparagine and 3,4-dihydroxyphenylalanine allowed differentiation of colonies of C. neoformans from C. albicans in 3 to 6 days. These data showed that pigment production from o- and p-diphenols served as an excellent biochemical test for the identification of C. neoformans.

Asparagine↗
PubMed2000

Evidence of zoonotic transmission of Cryptococcus neoformans from a pet cockatoo to an immunocompromised patient.

BACKGROUND: Although cryptococcosis has been associated with birds for almost 50 years, point sources for infection have not been identified. OBJECTIVE: To document zoonotic transmission of Cryptococcus neoformans. DESIGN: Case report. SETTING: A home in Boston, Massachusetts. PATIENT: A 72-year-old woman who received a diagnosis of cryptococcal meningitis in November 1998. The patient, who had been taking immunosuppressant drugs since undergoing renal transplantation in 1989, owned a pet cockatoo. MEASUREMENTS: Cryptococcus neoformans was isolated from the feces of the cockatoo. Isolates from excreta and from the patient were compared by using biochemical profiles, monoclonal antibody binding patterns, restriction fragment length polymorphism analysis, and karyotyping. RESULTS: The isolates from the patient and the cockatoo had identical biochemical profiles, the same monoclonal antibody immunofluorescence patterns, and indistinguishable patterns on restriction fragment length polymorphism analysis and karyotyping. CONCLUSIONS: The indistinguishable patient and cockatoo isolates strongly suggest that the patient's infection resulted from exposure to aerosolized cockatoo excreta. Although the incidence of cryptococcal infection due to such exposure is unknown, it may be prudent to advise immunocompromised patients to avoid pet birds and avian excreta.

Aged↗
PubMed1996

J774 murine macrophage-like cell interactions with Cryptococcus neoformans in the presence and absence of opsonins.

The interaction of Cryptococcus neoformans with the murine macrophage-like cell line J774.16 was studied in the presence and absence of monoclonal antibodies (MAbs) to the capsular polysaccharide glucuronoxylomannan (GXM). In the absence of MAb 2H1 to GXM, coincubation of J774.16 cells with C. neoformans reduced fungal colony-forming units in only 26.6% of 21 independent experiments. In the presence of MAb 2H1, coincubation of J774.16 cells with C. neoformans reduced fungal colony-forming units in > 95% of experiments. Comparison of the relative efficacy of two IgG1 MAbs revealed that the higher affinity MAb was more effective at low concentrations. Antibody-mediated reductions of C. neoformans colony-forming units by J774.16 cells occurred despite inhibition of nitric oxide synthase, addition of reactive oxygen intermediate scavengers, or the use of a superoxide-deficient J774 mutant line.

Animals↗
PubMed1997

Chloroquine induces human mononuclear phagocytes to inhibit and kill Cryptococcus neoformans by a mechanism independent of iron deprivation.

Infections due to Cryptococcus neoformans are common in AIDS patients. We investigated the effect of chloroquine, which raises the pH of phagolysosomes, on the anticryptococcal activity of mononuclear phagocytes. C. neoformans multiplied within monocyte-derived macrophages (MDM) in the absence of chloroquine but were killed with the addition of chloroquine. Ammonium chloride was also beneficial, suggesting that effects were mediated by alkalinizing the phagolysosome. Chloroquine inhibits growth of other intracellular pathogens by limiting iron availability. However, chloroquine-induced augmentation of MDM anticryptococcal activity was unaffected by iron nitriloacetate, demonstrating that chloroquine worked by a mechanism independent of iron deprivation. There was an inverse correlation between growth of C. neoformans in cell-free media and pH, suggesting that some of the effect of chloroquine on the anticryptococcal activity of MDM could be explained by relatively poor growth at higher pH. Chloroquine enhanced MDM anticryptococcal activity against all tested cryptococcal strains except for one large-capsule strain which was not phagocytosed. Positive effects of chloroquine were also seen in monocytes from both HIV-infected and -uninfected donors. Finally, chloroquine was therapeutic in experimental cryptococcosis in outbred and severe combined immunodeficient mice. Thus, chloroquine enhances the activity of mononuclear phagocytes against C. neoformans by iron-independent, pH-dependent mechanisms and is therapeutic in murine models of cryptococcosis. Chloroquine might have clinical utility for the prophylaxis and treatment of human cryptococcosis.

Ammonium Chloride↗
PubMed2006

Detection of Cryptococcus neoformans in bird excreta.

We evaluated 14 samples of bird excreta from pigeons, parrots, open billed storks and crows obtained from thirteen places in Bangkok and nearby areas between April and July 2004. These bird excreta were examined for Cryptococcus neoformans by direct plating method to inspect their ability to grow at 37 degrees C. Capsule production was examined by Indian ink preparation. They were also tested for urease and phenoloxidase enzymes. Cryptococcus neoformans var neoformans was recovered from pigeon excreta in 9.09%. This implies those having impaired immunity may get this fungus from the environment.

Animals↗
PubMed2000

Mannitol-1-phosphate dehydrogenase from Cryptococcus neoformans is a zinc-containing long-chain alcohol/polyol dehydrogenase.

Cryptococcus neoformans, the causative agent of cryptococcosis, produces large amounts of mannitol in culture and in infected mammalian hosts. Although there is considerable indirect evidence that mannitol synthesis may be required for wild-type stress tolerance and virulence in C. neoformans, this hypothesis has not been tested directly. It has been proposed that mannitol-1-phosphate dehydrogenase (MPD) is required for fungal mannitol synthesis, but no MPD-deficient fungal mutants or cDNAs or genes encoding fungal MPDs have been described. Therefore, C. neoformans was purified from a 148 kDa homotetramer of 36 kDa subunits that catalysed the reaction mannitol1-phosphate+NAD--><--fructose 6-phosphate+NADH. Partial peptide sequences were used to isolate the corresponding cDNA and gene, and the deduced MPD protein was found to be homologous to the zinc-containing long-chain alcohol/polyol dehydrogenases. Lysates of Saccharomyces cerevisiae transformed with the cDNA of interest (but not vector-transformed controls) contained MPD catalytic activity. Lastly, Northern analyses demonstrated MPD mRNA in glucose- and mannitol-grown C. neoformans cells. Thus, MPD has been purified and characterized from C. neoformans, and the corresponding cDNA and gene (MPD1) cloned and sequenced. Availability of C. neoformans MPD1 should permit direct testing of the hypotheses that (i) MPD is required for mannitol biosynthesis and (ii) the ability to synthesize mannitol is essential for wild-type stress tolerance and virulence.

Alcohol Oxidoreductases↗
PubMed2000

Possible primary ecological niche of Cryptococcus neoformans.

To study hollows of living trees as natural habitats of Cryptococcus neoformans in an endemic area of cryptococcosis in the northeastern region of Brazil, samples of decaying wood were collected inside 32 hollows of living trees and plated on niger seed agar. Identification of C. neoformans was based upon morphological and physiological tests. Canavanine-glycine-bromothymol medium was used to screen the varieties and Crypto Check Iatron Kit to serotype the isolates. A total of 123 C. neoformans colonies were recovered from samples of six (18.5%) out of 32 hollow trees. C. neoformans var. neoformans and C. neoformans var. gattii were found occurring alone (pink shower tree, fig tree and pottery tree) or sharing the same hollow (pink shower tree). Long lasting positivity (19-36 months) and significant number of cfu of C. neoformans per gram of decaying wood (0.15-21.7 x 10(3) cfu g(-1)) inside hollows of pink shower tree, fig tree and pottery tree were observed, indicating colonization of these habitats by the fungus. For the first time, C. n. var. neoformans and C. n. var. gattii were found sharing the same natural biotope, thus establishing a possible link between them in their life cycle in nature and suggesting the primary natural niche for the species.

Colony Count, Microbial↗