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PubMed2000

CCR2 expression determines T1 versus T2 polarization during pulmonary Cryptococcus neoformans infection.

Pulmonary clearance of the encapsulated yeast Cryptococcus neoformans requires the development of T1-type immunity. The objective of this study was to determine the role of CCR2 in leukocyte recruitment and development of T1-type cell-mediated immunity during pulmonary C. neoformans infection. Intratracheal inoculation of C. neoformans into CCR2 knockout (CCR2-/-) mice produced a prolonged pulmonary infection (5000-fold CFU at 6 wk compared with CCR2+/+ mice) and significant dissemination to the spleen and brain (160- and 800-fold greater). In addition, CCR2 deficiency resulted in significantly reduced recruitment of macrophages (weeks 1-3) and CD8+ T cells (weeks 1-2) into the lungs. The immune response in CCR2-/- mice was characterized by chronic pulmonary eosinophilia, crystal deposition in the lungs, pulmonary leukocyte production of IL-4 and IL-5 but not IFN-gamma, lack of anticryptococcal delayed-type hypersensitivity, and high levels of serum IgE. These results demonstrate that expression of CCR2 is required for the development of a T1-type response to C. neoformans infection and lack of CCR2 results in a switch to a T2-type response. Thus, CCR2 plays a critical role in promoting the development of T1- over T2-type immune responses in the lung following cryptococcus infection.

Animals↗
PubMed1989

Virulence and antifungal susceptibility of environmental and clinical isolates of Cryptococcus neoformans from Puerto Rico.

Studies on the distribution, epidemiology and pathogenesis of Cryptococcus neoformans on the island of Puerto Rico are few. We have studied mouse virulence and in vitro antifungal susceptibility of 133 isolates of C. neoformans: 121 environmental and 12 clinical (9 from AIDS patients), that were isolated in Puerto Rico. In experimental CD-1 mice infected intravenously, the mean lethal dose 50% values (28 days) were greater than 5.2 x 10(6) and 1.1 x 10(5) cells/mouse for environmental and clinical isolates, respectively. Using an agar dilution assay, the minimum inhibitory concentrations of amphotericin B, ketoconazole and 5-fluorocytosine were comparable for environmental and clinical isolates in both yeast nitrogen dextrose base agar and Kimming's agar. These data suggest a difference in lethality for mice, but no difference in antifungal susceptibility of environmental and clinical isolates of C. neoformans obtained in Puerto Rico.

Animals↗
PubMed2003

Apoptosis induction by glucuronoxylomannan of Cryptococcus neoformans.

We studied the ability of glucuronoxylomannan (GXM), the major constituent of Cryptococcus neoformans capsular polysaccharide, to induce apoptosis in lymphocytes from normal rats. Spleen mononuclear cells (Smc) from normal rats treated with GXM for 24 h exhibited, in comparison with controls, an increased hypodiploidy in the DNA profile after staining with propidium iodide, as well as increased ladder-type DNA fragmentation in agarose gel electrophoresis and a high number of positive cells in the terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) reaction. Furthermore, increased hypodiploidy in the DNA profile was also observed in Smc expressing T-cell receptor (TCR +). We also studied the induction of apoptosis in lungs and spleens from rats in the immunosuppressor period of disseminated cryptococcosis. TUNEL labeling of lungs and spleens from rats obtained 14 days after infection with C. neoformans showed a large number of apoptotic cells. Our results provide strong cytometric, molecular and morphological evidence that apoptosis could be a previously unrecognized immunosuppressive property of GXM in vitro. This programmed cell death may be involved in the immunosuppression observed during C. neoformans infection.

Animals↗
PubMed1987

Cryptococcus neoformans var. gattii in Australia.

An examination of 45 clinical isolates of Cryptococcus neoformans revealed an unusually high incidence of C. neoformans var. gattii in South Australia (65%) and in the Northern Territory (95%). In assessing all the available data from Australian isolates of C. neoformans, there appeared to be an endemic focus for the incidence of C. neoformans var. gattii in the rural aboriginal population of the Northern Territory.

Australia↗
PubMed1966

Cryptococcus neoformans in pigeon feces in San Francisco.

Typical Cryptococcus neoformans was isolated from one of 10 specimens of pigeon feces collected in downtown San Francisco. This isolation from a small sample suggests considerable prevalence of this important pathogen and tends to confirm that it is ubiquitous.

Animals↗
PubMed1996

Proteins in the cell wall and membrane of Cryptococcus neoformans stimulate lymphocytes from both adults and fetal cord blood to proliferate.

Cryptococcus neoformans is an encapsulated yeast that infects patients who have defective cell-mediated immunity, including AIDS, but rarely infects individuals who have intact cell-mediated immunity. Studies of the immune response to C. neoformans have been hampered by a paucity of defined T-lymphocyte antigens, and hence, the understanding of the T-cell response is incomplete. The goal of this study was to separate C. neoformans into its component parts, determine whether those components stimulate lymphocyte proliferation, perform preliminary characterization of the proteins, and establish the potential mechanism of lymphocyte proliferation. The lymphocyte response to fungal culture medium, whole organisms, disrupted organisms, and the yeast intracellular fraction or cell wall and membrane was studied by determining thymidine incorporation and by determining the number of lymphocytes at various times after stimulation. The cell wall and membrane of C. neoformans stimulated lymphocyte proliferation, while the intracellular fraction and culture filtrate did not. The optimal response occurred on day 7 of incubation, with 4 x 10(5) peripheral blood mononuclear cells per well and with 13 microg of cryptococcal protein per ml. The number of lymphocytes increased with time in culture, indicating that thymidine incorporation was accompanied by proliferation. Proteinase K treatment of the cell wall and membrane abrogated lymphocyte proliferation, indicating that the molecule was a protein. [35S]methionine labeling, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and fluorography were performed to analyze the proteins contained in the cell wall and membrane, intracellular fraction, and culture filtrate. At least 18 discrete bands were resolved from the cell wall and membrane. Since a large percentage of healthy adults responded to the cryptococcal cell wall and membrane, a mitogenic effect was investigated by testing proliferation of fetal cord blood lymphocytes. The percentage of fetal samples that proliferated in response to the cell wall and membrane was similar to the percentage of fetal samples that proliferated in response to Staphylococcus enterotoxin B, a microbial mitogen. Thus, a protein in the cell wall and membrane of C. neoformans is a potent stimulant of lymphocyte proliferation and has mitogenic properties, which may have important implications for cell-mediated immunity to C. neoformans.

Adult↗
PubMed2006

[Current topics in molecular medical mycology: new-stream Cryptococcus neoformans and other pathogenic fungi studies].

Model yeast Saccharomyces cerevisiae and human genome projects have been completed and proteomics is a major focus in postgenomic and postsequence research in biology and medicine. In 2004, the genome project on pathogenic yeast Candida albicans was completed, as was the Cryptococcus neoformans genome in 2005. The Aspergillus fumigatus genome project is currently under way. To use molecular data, such as phylogenic analysis, pathogenic factor analysis, and proteomics-based drug discovery/development, proteome analysis of pathogenic fungi has been conducted globally. I summarize up-to-date information on new-stream Cryptococcus neoformans and other pathogenic fungi studies based on molecular medical mycology.

Aspergillus fumigatus↗
PubMed1997

[Isolation of Cryptococcus neoformans from environmental samples in Alicante].

A study of the incidence of Cryptococcus neoformans in Alicante was carried out in environmental samples from the cities of Alicante and Santa Pola. The samples were pigeons faeces and Eucalyptus camaldulensis tissues. This study shows that the prevalence of the yeast in faeces from captive pigeons is higher (81.5%) than in the same samples from urban pigeons (16.3%). Regarding the biotype and varieties, a 79.3% of the isolates belonged to C. neoformans, and all of them were C. neoformans var. neoformans. None of the E. camaldulensis samples showed C. neoformans growth, although some Cryptococcus laurentii strains were isolated from flowers.

English Abstract↗
PubMed2004

A Sch9 protein kinase homologue controlling virulence independently of the cAMP pathway in Cryptococcus neoformans.

The polysaccharide capsule is one of the established virulence factors in Cryptococcus neoformans that provides a barrier against the host-mediated immune response. Mutation of the gene encoding the Saccharomyces cerevisiae Sch9 protein kinase homologue resulted in cells with enlarged capsules in C. neoformans. Capsule production was abrogated in sch9 pka1 double mutants, indicating that protein kinase A (PKA) signaling is still necessary for capsule formation in sch9 mutants. The sch9 mutant also exhibited increased thermal tolerance, a phenotype similar to sch9 mutant strains of S. cerevisiae. In addition, the sch9 mutant was attenuated in mating and the highly encapsulated cells were attenuated in virulence, in contrast to the pkr1 mutant, lacking the regulatory subunit of protein kinase A, that produced similarly enlarged capsules yet was increased in virulence. Interestingly, the virulence for the sch9 mutant strain could be restored by introduction of a pkr1 mutation; and the sch9 pkr1 mutant strain was dramatically increased in size and capsule thickness, suggesting that Sch9 and PKA function via different targets involved in virulence. Our findings support a model in which Sch9 modulates capsule formation and contributes to the virulence of C. neoformans both independently of and in conjunction with the cAMP-PKA pathway.

Animals↗
PubMed2000

Identification of the MATa mating-type locus of Cryptococcus neoformans reveals a serotype A MATa strain thought to have been extinct.

Cryptococcus neoformans is an opportunistic fungal pathogen with a defined sexual cycle involving mating between haploid MATa and MATalpha cells. Here we describe the isolation of part of the MATa mating-type locus encoding a Ste20 kinase homolog, Ste20a. We show that the STE20a gene cosegregates with the MATa mating type in genetic crosses, maps within the mating-type locus on a 1.8-Mb chromosome, and is allelic with the MATalpha locus. We identify the first MATa isolate of the most common pathogenic variety of C. neoformans (serotype A, variety grubii) which had been thought to be extinct. This serotype A MATa strain is sterile, fails to produce mating pheromone, and is less virulent than a serotype A MATalpha strain in an animal model. Our studies illustrate an association of mating type with virulence and suggest that, like Candida albicans, pathogenic isolates of C. neoformans may be largely asexual.

Amino Acid Sequence↗
PubMed1994

Influence of molecular sizes of Cryptococcus neoformans capsular polysaccharide on phagocytosis.

The role of capsular polysaccharides (CPS) of Cryptococcus neoformans in phagocytosis by murine alveolar macrophages was investigated in four strains of C. neoformans serotype A, YC-11, YC-5, YC-27 and YC-13. Phagocytosis rates increased markedly after adding 10% mouse serum, compared to fetal calf serum. The reverse relation between capsular thickness of C. neoformans and phagocytosis by alveolar macrophages was observed except in YC-27, which had thin capsules and high virulence. The phagocytosis rate in mice serum was 17.3% in YC-11 (capsule thickness 2.8-3.5 microns), 39.8% in YC-5 (capsule size 0.8-1.5 microns), 20.3% in YC-27 (capsule size 0.6-1.1 microns), and 62.8% in YC-13 (capsule not detected microscopically). The CPS of YC-11, YC-5, and YC-27 analyzed by gel-filtration using CL-2B showed high molecular fractions near the void volume. However, the CPS of YC-13 showed only low molecular fractions. The widely eluted CPS of YC-11 was separated into 3 fractions and each fraction was added in the phagocytosis assay of YC-13. Phagocytosis was markedly suppressed particularly by the addition of a higher molecular fraction. These results suggest that phagocytosis of C. neoformans by alveolar macrophages is influenced by the molecular sizes of the CPS.

Animals↗
PubMed1996

The second capsule gene of cryptococcus neoformans, CAP64, is essential for virulence.

The extracellular polysaccharide capsule produced by Cryptococcus neoformans is essential for its pathogenicity. We have isolated and characterized a gene, (AP64, which is required for capsule formation. An encapsulated strain created by complementation of the cap64 mutation produced fatal infection of mice within 25 days, while the cap64 acapsular strain was avirulent. Gene deletion of CAP64 from a wild-type strain resulted in the loss of capsule as well as virulence. Contour-clamped homogeneous electric field gel analysis indicates that CAP64 is located on chromosome III which is different from the localization of another capsule-related gene, CAP59. The nonlinkage between CAP64 and CAP59 was also supported by classical recombinational analysis. Database searches did not reveal any sequence with high similarity to CAP64. We also found that the CAP64 locus is contiguous to a convergently transcribed gene which has significant similarity to the gene encoding the yeast proteasome subunit, PRE1. The distance between the cDNA ends of these two genes is only 22 bp. This study confirms the previous molecular genetic evidence that capsule is an essential factor for the virulence of C. neoformans in the murine model.

Amino Acid Sequence↗
PubMed1986

Thermal death potentiation by amphotericin B in Cryptococcus neoformans and its dependence on pre-incubation temperature.

Thermal death of Cryptococcus neoformans in the presence of amphotericin B was strongly dependent upon the temperature of pre-incubation. The entropy coefficient, that is, the increase in entropy of activation of thermal death per square unit concentration of the drug in the medium, was 35 times higher after pre-incubation at 25 degrees C than at 39 degrees C. This means that C. neoformans cells grown at lower temperatures were much more sensitive to the temperature-dependent fungicidal effect of amphotericin B.

Amphotericin B↗
PubMed2003

[Avian habitats as sources of Cryptococcus neoformans in the city of Campo Grande, Mato Grosso do Sul, Brazil].

Cryptococcus neoformans is an encapsulated yeast agent of human and animal cryptococcosis. The variety neoformans is an important cause of mortality in AIDS-patients throughout the world. It has already been isolated worldwide from different environmental sources, including avian habitats. However, in spite of the occurrence of human cases of cryptococcosis, there are no studies on the ecology of this agent in the Brazilian Central-Western region. To study saprophytic sources of C. neoformans in the city of Campo Grande, 20 samples of avian droppings from distinct environments within the city were collected. The samples were suspended in sterile saline and then smeared on niger seed agar medium. Five days later smooth dark-brown colonies were subcultivated for identification by morphophysiologic tests. The variety and serotype was determined. C. neoformans var. neoformans serotype A was isolated from 10 (50%) of the samples collected. Consequently, the saprophytic presence of C. neoformans is related to avian habitats.

Animals↗
PubMed2006

Cryptococcus neoformans can utilize the bacterial melanin precursor homogentisic acid for fungal melanogenesis.

Cryptococcus neoformans melanizes in the environment and in mammalian tissues, but the process of melanization in either venue is mysterious given that this microbe produces melanin only from exogenous substrates. Understanding the process of melanization is important because melanization is believed to protect against various stresses in the environment, including UV radiation, and pigment production is associated with virulence. Melanization in C. neoformans requires the availability of diphenolic precursors. In contrast, many bacteria synthesize melanin from homogentisic acid (HGA). We report that C. neoformans strains representing all four serotypes can produce a brown pigment from HGA. The brown pigment was acid resistant and had the electron paramagnetic resonance spectrum of a stable free radical, qualities that identified it as a melanin. Melanin "ghost"-like particles obtained from pigmented C. neoformans cells were hydrophobic, fluorescent under a variety of irradiation wavelengths, negatively charged, insoluble in organic solvents and alcohols, resistant to degradation by strong acids, and vulnerable to bleaching. HGA melanization was laccase dependent and repressed by high concentrations of glucose. The ability of C. neoformans to utilize a bacterial melanin precursor compound suggests a new substrate source for melanization in the environment.

Animals↗
PubMed2005

Antibody-mediated protection against Cryptococcus neoformans pulmonary infection is dependent on B cells.

The pathogenesis of pulmonary Cryptococcus neoformans infection and the efficacy of passive immunoglobulin G1 (IgG1) administration were investigated in B-cell-deficient and C57BL/6J mice. C57BL/6J mice lived longer than B-cell-deficient mice after both intratracheal and intravenous infections. Administration of IgG1 prior to infection prolonged the survival of C57BL/6J mice but had no effect on the survival or numbers of CFU in the lungs of B-cell-deficient mice. C. neoformans infection in B-cell-deficient mice resulted in significantly higher levels of gamma interferon (IFN-gamma), monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein-1alpha (MIP-1alpha) than in C57BL/6J mice. IgG1 administration reduced IFN-gamma and MCP-1 levels in C57BL/6J mice but not in B-cell-deficient mice. In addition, compared to its effect in C57BL/6J mice, C. neoformans infection in FcRgammaIII-deficient, athymic, and SCID mice significantly increased IFN-gamma and MCP-1 levels. IgG1 administration was associated with reduced IFN-gamma levels in C57BL/6J mice but not in FcRgammaIII-deficient, athymic, and SCID mice. These observations suggest that IgG1-mediated protection in this system is a consequence of alterations in the inflammatory response that translate into less damage to the host without directly reducing the fungal burden. For hosts with impaired immunities, the ineffectiveness of passive antibody (Ab) may reflect an inability to down-regulate inflammation and avoid self-damage. The results indicate an important role for B cells in host defense against C. neoformans infection and demonstrate a surprising dependence of Ab-mediated protection on B cells in this system.

Animals↗
PubMed2003

OX40 ligation on activated T cells enhances the control of Cryptococcus neoformans and reduces pulmonary eosinophilia.

Pulmonary eosinophilia induced in C57BL/6 mice after Cryptococcus neoformans infection is driven by CD4(+) Th2 cells. The immunological mechanisms that protect against eosinophilia are not fully understood. Interaction of OX40 (CD134) and its ligand, OX40L, has been implicated in T cell activation and cell migration. Unlike CD28, OX40 is only expressed on T cells 1-2 days after Ag activation. Manipulation of this pathway would therefore target recently activated T cells, leaving the naive repertoire unaffected. In this study, we show that engagement of OX40 by an OX40L:Ig fusion protein drives IFN-gamma production by CD4(+) T cells and reduces eosinophilia and C. neoformans burden in the lung. Using gene-depleted mice, we show that reduction of eosinophilia and pathogen burden requires IL-12 and/or IFN-gamma. C. neoformans infection itself only partially induces OX40L expression by APCs. Provision of exogenous OX40L reveals a critical role of this pathway in the prevention of C. neoformans-induced eosinophilia.

Adjuvants, Immunologic↗
PubMed1997

Fungicidal mechanism of action of D0870 against Cryptococcus neoformans under acidic conditions.

The fungicidal mechanism of the triazole D0870 against Cryptococcus neoformans under acidic conditions was investigated. D0870 reduced the intracellular K+ content of C. neoformans at pH 4 to about half the value at pH 7 after 12 h of incubation. The 50% inhibitory concentrations of D0870 for ergosterol biosynthesis were almost the same at both pH 4 (0.017 microg/ml) and 7 (0.014 microg/ml); however, D0870 caused a marked accumulation of an unknown lipid and methylated sterols in C. neoformans cultured at pH 4. Extracted fractions containing the unknown lipid or methylated sterols showed strong fungicidal activities against C. neoformans both at pH 4 and 7 in phosphate-citrate buffer not containing D0870. Gas chromatographic-mass spectrometric analysis showed that the unknown lipid was obtusifolione. These results suggest that D0870 kills C. neoformans by disturbing the permeability of the cell membrane through the accumulation of obtusifolione and methylated sterols in the cell membrane under acidic conditions.

Antifungal Agents↗