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PubMed1978

Epidemiology of Cryptococcus neoformans.

The concept of the epidemiology of Cryptococcus neoformans as the causative agent of cryptococcosis and as a basidiomycetous yeast is based on the fact that bird manure has been until now its only known habitat but not plant material which likewise harbours various nonpathogenic Cryptococcus species. It could be shown that the possible influence of nutritional factors on the morphology and morphogenesis earns attention not only in view of the epidemiology of C. neoformans but of its perfect states, too.

Animals↗

PubMed1990

An anti-Cryptococcus neoformans monoclonal antibody directed against galactoxylomannan.

Six monoclonal antibodies (mAb) were produced by immunizing mice with a Cryptococcus neoformans serotype A spheroplast lysate (CNSL). Two mAb were of the IgG1 isotype; the others were IgM. The results obtained with one IgM mAb (CN6) are reported herein. This mAb recognized the four serotypes of C. neoformans and no cross-reactions were observed with extracts from Cryptococcus melibiosum, Candida albicans, Saccharomyces cerevisiae, Torulopsis glabrata or Trichosporon beigelii. Fractionation of the CNSL by gel filtration revealed that mAb CN6 recognized high molecular weight substances as well as a range of smaller molecules. Indirect ELISA inhibition studies showed that this mAb recognized substances in a cryptococcal culture filtrate. Inhibition studies and agglutination tests using latex beads sensitized with purified CN6 showed that CN6 strongly reacted with the C. neoformans serotype A cell envelope galactoxylomannan-mannoprotein complex (GAlXM-MP) and only weakly with the glucuronoxylomannan (GXM) component. These tests also showed that purified galactoxylomannan (GalXM) from C. neoformans serotype A was more reactive than purified mannoprotein (MP). An anti-GalXM mAb might be a useful tool for monitoring the clinical course of cryptococcal infections.

Animals↗

PubMed1979

Survey of Cryptococcus neoformans in the respiratory tract of patients with bronchopulmonary disorders and in the air.

Cryptococcus neoformans was cultured from 9 (1%) of 835 clinical specimens examined from the respiratory tract of patients. These isolations came from 3 (0.4%) of the760 patients; 8 isolates were from sputum and one from urine. The fungus was not demonstrable in the air at a selected site during a 2-year study although other species of Cryptococcus, namely, C. albidus, C. ater, C. flavus, C. laurentii, C. magnus, C. terreus and C. uniguttulatus were isolated. The three C. neoformans positive patients were males, with pulmonary tuberculosis as the primary disease and history of repeated exposure to pigeon excreta in two. None of these patients manifested any overt signs and symptoms specificially attributable to cryptococcosis, nor did they receive any antifungal therapy. Repeated isolations of C. neoformans from sputum, a positive urine culture and demonstration of cryptococcal antibodies in a serum specimen, followed by negative cultures and serology, suggested that patient 1 had spontaneously recovered from an episode of benign, minimal pulmonary cryptococcosis. Patients 2 and 3 probably carried the fungus as a transient resident of the respiratory tract. The results suggest that C. neoformans is of uncommon occurrence in the respiratory tract of patients with bronchopulmonary disorders and that the isolation of the fungus from this site may not necessarily imply an etiologic relationship.

Adult↗

PubMed1975

Combined activity of amphotericin B and 5-fluorocytosine against Cryptococcus neoformans in vitro and in vivo in mice.

The in vitro and in vivo activities of amphotericin B and 5-fluorocytosine (5-FC) alone and in combination were studied to determine possible drug interactions against two strains of Cryptococcus neoformans, one sensitive to 5-FC and one resistant to 5-FC. In vitro tube dilution studies demonstrated only additive effects with the 5-FC-sensitive organism but antagonism with eth 5-FC-resistant organism. A mouse model of cryptococcal meningitis allowed comparative drug trails in a new model for the detection of drug interactions. Drug combinations were no more effective against meningitis caused by the 5-FC-sensitive organism than the additive effects of the individual drugs. However, meningitis caused by the 5-FC-resistant Cryptococcus responded less to drug combinations than to either drug alone. Serum levels of amphotericin B and 5-FC were comparable in all groups. No evidence of toxicity from the drug combinations was found. No inhibition of development of resistance to 5-FC by the combination with amphotericin B was detected.

Amphotericin B↗

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↗

PubMed1991

Normally saprobic cryptococci isolated from Cryptococcus neoformans infections.

We report two cases in which Cryptococcus laurentii was isolated from surgically resected pulmonary lesions but the cryptococcal cells is tissue reacted positively with a specific fluorescent antibody (FA) conjugate for Cryptococcus neoformans. Both patients had no apparent host defense defects. In both cases, multiple cryptococcal isolates were obtained from tissue, and yeastlike cells consistent with C. neoformans were seen in direct histology. The isolates were identified by assimilation patterns and standard procedures including phenoloxidase reactions. Since C. laurentii was consistently isolated by using stringent procedures, it was considered unlikely that the fungus represented surgical or laboratory contamination. Its presence may be the result of dual infection not detected by FA, but other possible explanations exist. The results show the value of the FA test in diagnostic mycology and call into question previous reports of cryptococci other than C. neoformans as agents of infection.

Adult↗

PubMed1978

Rapid presumptive identification of Cryptococcus neoformans.

Carbohydrate-containing extracts were prepared from mature yeast colonies grown on Sabouraud dextrose agar by mixing a 0.001-ml loopful of yeast cells for 30 s in phenolized saline and removing the cells by centrifugation. Extracts were prepared from 54 Cryptococcus neoformans isolates, 29 isolates of other Cryptococcus species, 16 isolates of Candida species, 2 Rhodotorula, 2 Torulopsis, and 1 Saccharomyces species. Initially the carbohydrate content of each extract was estimated (Molisch method) and adjusted to 1, 5, and 10 microgram/ml. Twofold dilutions of each extract were tested for reactivity with the cryptococcal latex agglutination reagent of Bloomfield et al. (N. Bloomfield, M.A. Gordon, and D.F. Elmendorf, Jr., Proc. Soc. Exp. Biol. Med. 114:64-67, 1963). All 54 C. neoformans extracts gave strong agglutinations (3+ to 4+) in dilutions of 1:4 or greater. None of the other yeasts produced any agglutination, except for 1 of 15 C. laurentii isolates, which showed a 1+ reaction that disappeared at a dilution of 1:4 and above. Subsequent testing established that a single extract made from 0.001 ml of yeast cells in 6 ml of phenolized saline contained less than 5 microgram of carbohydrate per ml, was suitable for a single rapid screening dilution, and eliminated any cross-reaction from the C. laurentii isolates. In our hands this method has provided a reliable differentiation of C. neoformans from other unknown yeast colonies in less than 20 min exclusive of a Molisch determination.

Candida↗

PubMed1990

Utilization by yeasts of D-glucarate, galactarate, and L-tartarate is uncommon and occurs in strains of Cryptococcus and Trichosporon.

In 38 yeast genera tested, utilization of D-glucarate was uncommon, occurring with only 10 strains out of 373. The ability was prominent among Cryptococcus strains, with 8 out of 8 tested being positive, including the pathogen Cryptococcus neoformans. The ability was present also in Trichosporon where 2 out of the 4 strains tested were positive. There was a correlation between ability to utilize D-glucarate, galactarate, L-tartarate, and D-glucuronate. Use of L-ascorbate occurred in more genera than use of D-glucarate, but all strains that grew on D-glucarate grew on L-ascorbate. The utilization of certain hydroxylated carboxylates by strains, mainly found in two genera, is of interest in identifying the catabolic pathways involved, in taxonomic studies, and in developing rapid methods of yeast identification.

Ascorbic Acid↗

PubMed1976

Six-hour pigmentation test for the identification of Cryptococcus neoformans.

Cryptococcus neoformans colonies can be identified within 6 h using paper disks containing caffeic acid and ferric citrate. Indentification is based on the development of a dark brown pigment. Saprophytic Cryptococcus species and common clinically isolated yeasts do not develop the brown color. The concentration of the reagents and the method of storage of the impregnated paper disks are critical for the rapid and specific development of the pigment.

Caffeic Acids↗

PubMed1990

Polyamine depletion and growth inhibition of Cryptococcus neoformans by alpha-difluoromethylornithine and cyclohexylamine.

The ability of two known inhibitors of polyamine synthesis alpha-difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase (ODC), and cyclohexylamine, an inhibitor of spermidine synthase, to inhibit the in vitro growth and polyamine synthesis of clinical isolates of Cryptococcus neoformans was examined. Treatment of C. neoformans with either DFMO or cyclohexylamine resulted in depletion of cellular polyamines and inhibition of growth. Cryptococcus neoformans was shown to lack detectable spermine and to require high concentrations of spermidine, but not putrescine, for growth. The growth inhibition by DFMO and cyclohexylamine was reversed by exogenous polyamines. These findings document the ability of cyclohexylamine and DFMO to inhibit polyamine synthesis and growth in clinically important isolates of C. neoformans.

Cryptococcus neoformans↗

PubMed1991

Immunity to a pulmonary Cryptococcus neoformans infection requires both CD4+ and CD8+ T cells.

The role of CD4+ and CD8+ T cells in mediating pulmonary clearance of a cryptococcal infection was investigated. Intratracheal inoculation of BALB/c and C.B-17 mice with a moderately virulent strain of Cryptococcus neoformans (52D) resulted in a pulmonary infection, which was cleared by a T cell-dependent mechanism. During this clearance, there was a significant influx of both CD4+ and CD8+ T cells into the lungs. Depletion of CD4+ T cells by injections of CD4-specific monoclonal antibody (mAb) prevented pulmonary clearance and also resulted in significant colonization of the brain and spleen of infected mice. CD4 depletion did not prevent the influx of CD8+ T cells into the lungs. Surprisingly, depletion of CD8+ T cells by mAb also ablated pulmonary clearance. CD8-depleted mice also had a small but significant increase in brain and spleen colony-forming unit compared to control mice by the end of the study. CD4+ T cell pulmonary influx was independent of the presence of CD8+ T cells. The lungs of T cell-depleted mice were examined histologically. CD4+ and CD8+ T cells each mediated a degree of inflammatory influx seen in the lungs of infected mice and raised the possibility that CD4+ and CD8+ T cells may synergize to generate the inflammatory response in the lungs. Numerous phagocytized but intact cryptococci were seen in the inflammatory foci of CD8-depleted mice but not in control or CD4-depleted mice. We propose that CD4+ T cells may recruit and activate effector phagocytes while CD8+ T cells predominantly function to lyse cryptococcus-laden unactivated phagocytes similar to the function of CD8+ T cells during listeria and mycobacteria infections.

Animals↗

PubMed1992

CD4+ T cells cause multinucleated giant cells to form around Cryptococcus neoformans and confine the yeast within the primary site of infection in the respiratory tract.

The possible mechanisms by which CD4+ T cells prevent the dissemination of Cryptococcus neoformans from the primary site of infection in the respiratory tract were examined. It was found that even before fungicidal mechanisms are fully induced in the lungs, the host generates a CD4+ T cell-dependent inflammatory response that sequesters yeast within the pulmonary alveoli. This confinement is evident histopathologically and demonstrable objectively as a rapid decline in the ability to dislodge yeast from the lungs by bronchopulmonary lavage. One striking component of this response is the enclosure of cryptococci within multinucleated giant cells in granulomas. Studies in severe combined immunodeficient mice that were engrafted with selected lymphocyte subpopulations show that B cells, and hence anti-Cryptococcus antibodies, are not necessary for the CD4+ T cell-dependent responses that isolate and subsequently destroy this opportunistic pathogen in the lung parenchyma.

Animals↗

PubMedDate not supplied

The ecology of Cryptococcus neoformans and the epidemiology of cryptococcosis.

The ecology of Cryptococcus neoformans and the epidemiology of cryptococcosis are reviewed. Two varieties of C. neoformans have been recognized. C. neoformans variety neoformans has been found in nature worldwide, primarily in association with bird droppings, although nonavian sources have also been found. Most cases of human cryptococcosis are caused by this variety. C. neoformans var. gattii has recently been isolated in nature in association with Eucalyptus trees. Infections caused by this variety occur mainly in tropical and subtropical regions. Because exposure to C. neoformans is probably common and clinically apparent cases of cryptococcosis in healthy hosts are rare, it is presumed that most people can mount adequate host defenses upon exposure to the organism. At least 5%-10% of patients with AIDS become infected with Cryptococcus; the epidemiology of this infection is different in many respects from that seen in patients without AIDS.

Acquired Immunodeficiency Syndrome↗

PubMed1992

Virulence, serotype, and molecular characteristics of environmental strains of Cryptococcus neoformans var. gattii.

Four strains of Cryptococcus neoformans var. gattii originating from Eucalyptus camaldulensis, three from Australia and one from San Francisco, were tested for their serotype, virulence for mice, and a number of genetic and molecular characteristics. All were found to be serotype B and showed significantly higher virulence for mice than did the type strains of C. neoformans var. gattii and Filobasidiella neoformans var. bacillispora, which were obtained from human cryptococcosis cases. Electrophoretic karyotypes of the strains from Australia were identical, although they were collected from sites at least 15 to 500 km apart. The electrophoretic karyotype of the strain from San Francisco was the same as that of the Australian isolates except for the mobility of one chromosome. On the contrary, no two isolates of serotype B (of a total of 11) from clinical sources were the same, regardless of their geographic origin. Furthermore, none of the clinical isolates showed a chromosomal banding pattern identical to that of Eucalyptus-originated strains. The Eucalyptus-originated strains failed to form dikaryons when crossed with the tester strains of the two varieties of F. neoformans. Hybridization analysis with a nucleic acid probe (AccuProbe C. neoformans Culture Confirmation Test; Gen-Probe Inc., San Diego, Calif.), however, showed signals of equal intensity for clinical strains and the Eucalyptus-originated strains. Various fungi phylogenetically related to C. neoformans, including a phenol oxidase-positive strain of Cryptococcus laurentii obtained from E. camaldulensis, were negative in the nucleic acid hybridization test. These observations confirm that, in spite of karyotypic differences and the lack of dikaryon formation with the tester strains of F. neoformans, Eucalyptus-originated C. neoformans var. gattii is the same organism as those isolated from cases of human infection. Furthermore, the C. neoformans culture confirmation test using a commercial nucleic acid probe is specific for C. neoformans.

Animals↗

PubMed1976

Production of extracellular ribonuclease by yeasts and yeastlike fungi, and its repression by orthophosphate in species of Cryptococcus and Tremella.

A strain of Cryptococcus laurentii and a haploid isolate of Tremella foliacea were shown to produce orthophosphate-repressible ribonuclease in liquid culture. Addition of as little as 1 mM K2HPO4, pH 7.0, completely repressed enzyme production by both fungi. The orthophosphate-repressible enzyme was not produced by other species of the two genera tested. These results, together with other findings, suggest a close phylogenetic relationship between Cryptococcus laurentii and Tremella foliacea. The ability of other yeasts and yeastlike fungi to hydrolyze ribonucleic acid in a solid test medium was assessed. Based on the limited number of organisms available for study, extracellular ribonuclease activity was found in species having close affinity to the Basidiomycetes and in yeasts classified in the ascomycetous genera, Endomycopsis, Hansenula, and Kluyveromyces. Other ascomycetous yeasts did not exhibit extracellular ribonuclease.

Ascomycota↗

PubMed1991

Evaluation of a new method for identification of Cryptococcus neoformans which uses serologic tests aided by selected biological tests.

A new method for identifying Cryptococcus neoformans isolates and their serotypes by the slide agglutination test using five kinds of factor sera, with the aid of nitrate reduction, phenol oxidase, and growth at 37 degrees C tests was evaluated by using 36 reference strains and 75 clinical isolates of C. neoformans. The results showed that the reference strains were identified exactly as they were labeled, and clinical isolates were identified as C. neoformans serotypes A, D, and AD. C. neoformans could be distinguished from other Cryptococcus species that cross-reacted with factor sera by their ability to grow at 37 degrees C. These results indicate that the slide agglutination test combined the use of factor sera for isolates which grow at 37 degrees C is a useful method for identification of C. neoformans and their serotypes and that the nitrate reduction test (negative in 100% of the isolates) and the phenol oxidase test (positive in approximately 95% of the isolates) can be used to confirm that the species is C. neoformans.

Agglutination Tests↗

PubMed1991

Rapid clearance of Candida albicans mannan antigens by liver and spleen in contrast to prolonged circulation of Cryptococcus neoformans antigens.

Clearances of mannan antigen from Candida albicans and glucuronoxylomannan antigen from Cryptococcus neoformans were examined in nonimmune rabbits by using self-prepared latex agglutination tests. Injected intravenously, 20 mg of Candida mannan antigen was cleared from the serum with a half-life of approximately 2 h. In contrast, 20 micrograms of Cryptococcus glucuronoxylomannan antigen had a half-life in serum of approximately 24 h. At the latest, 9 h after injection, both antigens were no longer detectable without pretreatment of serum samples with protease and heating to 100 degrees C, thus indicating rapid binding by serum proteins other than immunoglobulins. Candida mannan antigen clearance was also examined in nonimmune mice after intravenous injection of (i) 200 micrograms of Candida mannan antigen, which accumulated in the liver and spleen and persisted for 97 days; (ii) 2 x 10(7) ethanol-killed Candida blastospores, which was accompanied by rapid clearance of mannan from the blood but accumulation of mannan in the liver and spleen and slow clearance from these organs; (iii) 6 x 10(6) viable C. albicans cells (lethal infection), which resulted in a rapid decrease of Candida CFU in the blood, liver, and spleen during the first 8 h, after which blood cultures were negative on day 2 and viable Candida burdens in the liver and spleen persisted at 10(5) CFU/g, whereas Candida mannan antigen continued to circulate in the bloodstream and accumulated in the liver and spleen.

Animals↗

PubMed2026

Distinct STRIPAK subunits drive conserved and subunit-specific signaling programs in Cryptococcus neoformans.

The striatin-interacting phosphatase and kinase (STRIPAK) complex is a conserved protein phosphatase 2A (PP2A)-associated signaling hub that integrates kinase-phosphatase networks, yet its roles in human fungal pathogens remain poorly defined. Here, we dissected STRIPAK functions in the opportunistic pathogen Cryptococcus neoformans by combining genetic, genomic, virulence, and phosphoproteomic analyses across mutants lacking individual STRIPAK subunits. Loss of the core STRIPAK components via PPH22, FAR8, FAR9, or FAR11 mutations caused severe defects in growth, stress adaptation, cell cycle progression, and morphogenesis, accompanied by widespread aneuploidy and genome instability. In murine infection models, far11Δ strains were avirulent, whereas far9Δ mutants caused delayed but ultimately fatal disease and underwent host-associated genome remodeling, with recovered isolates exhibiting chromosome 11 amplification despite no consistent in vitro fitness advantage. In contrast, deletion of MOB3 produced a hypervirulent phenotype. mob3Δ cells exhibited enhanced transmigration across an in vitro blood-brain barrier model, increased survival in macrophages, and generated small-cell morphotypes, features associated with increased dissemination. Phosphoproteomic profiling revealed extensive and overlapping phosphorylation changes among core STRIPAK mutants, affecting pathways involved in signaling, cytoskeletal, cell cycle control, chromatin regulation, RNA metabolism, and stress responses. Conversely, mob3Δ mutants displayed a smaller, largely distinct phosphoproteomic signature. Network and functional enrichment analyses highlighted STRIPAK-dependent regulation of TORC2-associated signaling, MAPK/GTPase signaling, autophagy, nuclear transport, RNA processing, DNA replication, and ribosome biogenesis. Together, these findings establish STRIPAK as a coordinator of genome stability, morphological plasticity, stress adaptation, and virulence in C. neoformans, and demonstrate that individual STRIPAK subunits drive shared yet divergent signaling outputs that shape host-pathogen interactions.IMPORTANCEFungal pathogens must rapidly adapt their growth, morphology, and stress responses to survive within the host, requiring precise coordination of cellular signaling pathways. The conserved striatin-interacting phosphatase and kinase (STRIPAK) complex controls key developmental programs in eukaryotes, but its roles in fungal pathogenesis are not fully defined. We previously showed that STRIPAK is important for genome stability, development, and virulence in the opportunistic human fungal pathogen Cryptococcus neoformans. Here, we define how individual STRIPAK subunits differentially regulate fungal morphogenesis, genome plasticity, host adaptation, and virulence, revealing both shared and subunit-specific functions within this conserved signaling complex. Core STRIPAK mutants exhibit severe growth and stress-response defects and attenuation of virulence, whereas loss of the Mob3 subunit promotes hypervirulence by enhancing dissemination and persistence within the host. Phosphoproteomic profiling reveals that individual STRIPAK components exert shared yet distinct control over phosphorylation networks that shape host-pathogen interactions, establishing STRIPAK as a central signaling hub and a potential target for antifungal intervention.

Cryptococcus neoformans↗