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PubMed1983

Immunization of mice with stable, acapsular, yeast-like mutants of Cryptococcus neoformans.

Immune responses, including lymphocyte transformation and protection, were evaluated in a new model of experimental murine cryptococcosis. Newly developed, genetically stable, acapsular mutants of Cryptococcus neoformans were used to immunize C3H/HeN mice. Intraperitoneal and subcutaneous routes of immunization without adjuvant were studied. Spleen cells and pooled popliteal and inguinal lymph node cells responded significantly to heat-killed, whole-cell C. neoformans antigen but not to Candida albicans antigen in lymphocyte transformation assays. No significant difference in lymphocyte transformation response to antigens was observed between intraperitoneally and subcutaneously immunized animals. Mean survival time of immunized mice was extended significantly in comparison to controls following intravenous challenge with virulent C. neoformans. Degree of protection was independent of route of immunization but dependent upon the magnitude of the challenge inoculum. This model should prove valuable in the study of immunoregulation of cryptococcosis and vaccine development.

Animals↗
PubMed1976

Immunization of mice with a mutant of Cryptococcus neoformans. Characterization of the mutant, actively acquired resistance to experimental cryptococcosis in mice.

In 69% of subdermally and 50% of subcutaneously immunized mice, immunity against Cryptococcus neoformans was obtained. The vaccine consisted of a gamma-irradiated mutant, which grew well at 5 degree C and at room temperature. Many subcultures and animal passages did not restore this mutant to the encapsulated, pathogenic wild type.

Animals↗
PubMed2003

Glucuronoxylomannan of Cryptococcus neoformans exacerbates in vitro yeast cell growth by interleukin 10-dependent inhibition of CD4+ T lymphocyte responses.

Glucuronoxylomannan (GXM), the major capsular polysaccharide of Cryptococcus neoformans, is the most important virulence factor of this fungus. We analyzed the molecular events related to protective immune responses against a non-encapsulated strain of C. neoformans, mediated by murine splenic CD4(+) T lymphocytes in vitro, and the impact of GXM addition upon these events. Both the lymphoproliferation of CD4(+) T cells and the control of fungus growth were dependent on B7 co-stimulation. Addition of GXM did not modify CD4(+) T cell proliferation, but exacerbated infection in cultures obtained from normal and infected hosts. GXM enhanced the secretion of IL-10 and IL-4, while it reduced the production of pro-inflammatory cytokines TNF-alpha and IFN-gamma. The blockade of IL-10 activity with neutralizing antibodies increased TNF-alpha production and reduced yeast cell growth. The findings suggest that GXM exacerbates infection by down-regulating cell-mediated protective immune response and that IL-10 is implicated in yeast evasion.

Animals↗
PubMed2002

Electron microscopy of pathogenic yeasts Cryptococcus neoformans and Exophiala dermatitidis by high-pressure freezing.

A high-pressure freezing method was used to observe the ultrastructure of pathogenic yeasts, Cryptococcus neoformans and Exophiala dermatitidis, after freeze-substitution and ultrathin sectioning. The method well preserved the cell structure in its natural state, since the capsule, cell wall, plasma membrane, nucleus, outer and inner nuclear membranes, nuclear pores, nucleolus, mitochondria, mitochondrial membrane and cristae, vacuoles, endoplasmic reticulum, Golgi apparatus, spindle pole body, ribosomes, lipid droplets, microtubules, actin filaments, and glycogen granules were clearly visible. The method was shown to freeze cells as deep as 0.1 mm by sectioning the sample perpendicular to specimen surface. The quality of the cell image was similar to that obtained by a rapid freezing method when compared using the same materials. Thus, high-pressure freezing would be useful for making serial ultrathin sections for three-dimensional analysis of cells, which should give basic information of structure and function of pathogenic yeast cells necessary for finding an effective therapy for mycoses.

Cryopreservation↗
PubMed1976

Caffeic acid-containing medium for identification of Cryptococcus neoformans.

A new growth medium containing caffeic acid and ferric citrate is described. The pigment produced on this medium is specific for the identification of Cryptococcus neoformans and differentiates it from other cryptococci. The medium is more easily compounded and requires less time for pigment formation than the conventional Guizotia extract media. The medium is stable in the dry form as well as in the prepared form.

Caffeic Acids↗
PubMed1995

Sensitivity of sandwich enzyme-linked immunosorbent assay for Cryptococcus neoformans polysaccharide antigen is dependent on the isotypes of the capture and detection antibodies.

Immunoglobulin M (IgM) and IgG1 monoclonal antibody isotype switch variants to Cryptococcus neoformans capsular polysaccharide were used to study the sensitivity of a double sandwich enzyme-linked immunosorbent assay (ELISA). The most sensitive ELISA configurations used IgG1 monoclonal antibody absorbed on polystyrene plates or IgM immobilized with goat antisera for antigen capture.

Animals↗
PubMed2000

Novel therapeutic approach by culture filtrate of Cryptococcus neoformans var. gattii (CneF) in experimental immune complex glomerulonephritis.

The present study was undertaken to determine the therapeutic effect of the culture filtrate of Cryptococcus neoformans var. gattii (CneF) in experimental immune complex glomerulonephritis. Bovine serum albumin (BSA) nephritis was induced in rats by a subcutaneous immunization and daily intravenous administration of BSA. CneF solution at three different doses (36, 54, and 90 mg/kg based on carbohydrate concentration) was administered intraperitoneally at regular 72-h intervals for 4 weeks. Onset of treatment was day 65, and urinary protein was measured at different intervals. Animals were euthanized on day 107. Serum and urine determinants were measured at the time of sacrifice and kidney specimens were examined. Results of this experiment showed that CneF therapy could significantly reduce the urinary protein excretion, blood urea nitrogen (BUN), plasma concentration of triglyceride, and increase the serum HDL cholesterol in treated rats vs. nontreated controls. Moreover, there was significant difference in glomerular changes between treated and nontreated groups. These observations show that the beneficial effect of CneF may be related to decreased number of glomerular leukocytes. Our findings suggest that treatment with CneF as a new antiinflammatory compound can reduce proteinuria, suppress the development of glomerular lesions, and exert lipid-lowering property in a rat model of immune complex glomerulonephritis.

Animals↗
PubMed2003

Cryptococcus neoformans with a mutation in the tetratricopeptide repeat-containing gene, CCN1, causes subcutaneous lesions but fails to cause systemic infection.

We studied a Cryptococcus neoformans strain that caused feline chronic nasal granuloma without disseminated disease. This strain, B-4551, grows at temperatures up to 35 degrees C and fails to cause systemic infection in mice. Many cells of B-4551 formed short hyphal elements in feline nasal tissue and occasionally at 35 degrees C in vitro. A complementation and sequence analysis revealed that the temperature-sensitive (Ts) phenotype of B-4551 was due to deletion of a lysine residue in the cryptococcal CCN1 gene. B-4551 complemented with the wild type CCN1 gene grew at 37 degrees C and caused fatal systemic infection in mice. The CCN1 gene encodes a protein containing 16 copies of a tetratricopeptide repeat. CCN1 is homologous to the Saccharomyces cerevisiae CLF1 gene, which is required for pre-mRNA splicing, cell cycle progression, and DNA replication, and to the Drosophila melanogaster crn gene, which is involved in neurogenesis. CLF1 complemented the Ts phenotype of B-4551. CCN1, however, failed to rescue the clf1 mutant in S. cerevisiae. These results indicate that the Ccn1p may not be as functionally diverse as Clf1p in yeast.

Amino Acid Sequence↗
PubMed2000

Temperature-sensitive strain of Cryptococcus neoformans producing hyphal elements in a feline nasal granuloma.

We report the isolation of a temperature-sensitive, serotype A, mating type alpha strain of Cryptococcus neoformans from a case of nasal cryptococcosis in a cat. The strain grew extremely slowly at 35 degrees C and failed to grow at 37 degrees C in vitro. Histopathological sections of the infected tissue revealed yeast cells producing hyphae up to several hundred micrometers in length, in addition to numerous encapsulated yeast cells typical of C. neoformans. The cultures grown on yeast extract-peptone-glucose agar at 35 degrees C also produced some yeast cells with germ tube-like hyphal elements up to 100 microm in length.

Animals↗
PubMed2004

Age-related resistance of C57BL/6 mice to Cryptococcus neoformans is dependent on maturation of NKT cells.

Conflicting results have been reported regarding the ability of C57BL/6 mice to clear infections due to Cryptococcus neoformans. Examination of the various experimental protocols used suggested that C57BL/6 mice might develop the ability to resist infection as they mature. We analyzed the ability of C57BL/6 mice of different ages to respond to immunization with cryptococcal antigen or to clear a cryptococcal infection. Mice were immunized with a soluble cryptococcal culture filtrate antigen (CneF) emulsified in complete Freund's adjuvant (CneF-CFA). Delayed-type hypersensitivity (DTH) reactions elicited by the immunization were significantly stronger in 15-week-old C57BL/6 mice than in 7-week-old mice. Analysis of cryptococcal CFU 8 weeks following intratracheal infection of 7-week-old mice or 15-week-old mice revealed a relative inability of the younger animals to control the infection. Six-week-old immunized and infected mice cleared cryptococci from brain, spleen, and liver in a manner similar to that of immunized and infected 15-week-old mice. However, the older mice cleared cryptococci much more efficiently from the lungs. The possible role for NKT cells was determined by passive transfer of thymocytes from 10-week-old mice (containing mature NKT cells) or 2-week-old mice (containing immature NKT cells) to 6-week-old mice. The 10-week-old thymocytes significantly enhanced the ability of the mice to develop a DTH response after immunization with CneF-CFA, while animals treated with 2-week-old thymocytes did not improve their DTH response after immunization. The cells in the 10-week-old thymocyte population responsible for improvement of DTH responses were identified as being NK1.1 positive.

Aging↗
PubMed2005

Efficacy of swabbing versus a conventional technique for isolation of Cryptococcus neoformans from decayed wood in tree trunk hollows.

The efficacy of swabbing versus a conventional sedimentation technique was evaluated for sampling of decayed wood in tree trunk hollows for isolation of Cryptococcus neoformans. Of 52 samples of decayed wood, bark or other plant debris originating from 35 living trees, 42 wood samples yielded C. neoformans. The positive samples included 40 collected from 31 Syzygium cumini trees growing along roadsides in Old Delhi, whereas the remaining two were from inside tree trunk fissures of Ficus religiosa in a New Delhi locality. The number of wood samples found positive by swabbing was 40 (95%) as opposed to 32 (76%) by the conventional technique, and this difference was statistically significant (P < 0.01). Also, the conventional technique showed 24% false-negative results, which was in striking contrast to only 5% by swabbing. Furthermore, swabbing yielded a significantly higher C. neoformans mean colony count than did the conventional technique (P < 0.005), thus highlighting greater efficacy of the former technique. The overall prevalence of C. neoformans in the S. cumini trees investigated was 84% (26/31 trees) which is the highest as yet reported from any tree species in India. Varietal identification and serotyping was done with 33 of the C. neoformans isolates, 31 of which came from 23 tree trunk hollows of S. cumini and two from the tree trunk fissures of F. religiosa. Among the S. cumini isolates, 26 were identified as C. neoformans var. gattii (all serotype B except two untypeable ones) and five as C. neoformans var. neoformans, serotype A (= C. neoformans var. grubii). Both of the F. religiosa isolates belonged to C. n. var. neoformans, serotype A. Being a more efficacious, simple, less time-consuming and less hazardous technique, swabbing is recommended for wider use in order to further elucidate the ecology of C. neoformans.

Biodegradation, Environmental↗
PubMed2005

Isolation of Cryptococcus neoformans var. grubii (serotype A) from pigeon droppings in Seoul, Korea.

Seventy-two pigeon dropping samples were collected from 26 different localities in Seoul and investigated for the occurrence of Cryptococcus neoformans. Seventeen samples from 8 different localities were found to be positive for C. neoformans. All isolates were obtained from withered pigeon droppings. Identification and serotyping of the isolates were determined by means of serological testing and DNA fingerprinting. All isolates belonged to C. neoformans var. grubbi (serotype A).

Animals↗
PubMed2000

Circulating soluble CD4 directly prevents host resistance and delayed-type hypersensitivity response to Cryptococcus neoformans in mice.

In the present study, we examined the effect of soluble CD4 (sCD4) on host resistance and delayed-type hypersensitivity (DTH) response to Cryptococcus neoformans using a novel mutant mouse that exhibits a defect in the expression of membrane-bound CD4 but secretes high levels of sCD4 in the serum. In these mice, host resistance to this pathogen was impaired as indicated by an increased number of live pathogens in the lung. To elucidate the mechanism of immunodeficiency, three different sets of experiments were conducted. First, administration of anti-CD4 mAb restored the attenuated host defense. Second, in CD4 gene-disrupted (CD4KO) mice, host resistance was not attenuated compared to control mice. Third, implantation of sCD4 gene-transfected myeloma cells rendered the CD4KO mice susceptible to this infection, while similar treatment with mock-transfected cells did not show such an effect. These results indicated that immunodeficiency in the mutant mice was attributed to the circulating sCD4 rather than to the lack of CD4+ T cells. In addition, DTH response to C. neoformans evaluated by footpad swelling was reduced in the mutant mice compared to that in the control, and the reduced response was restored by the administration of anti-CD4 mAb. Finally, serum levels of IFN-gamma, IL-12 and IL-18 in the mutant mice were significantly reduced, while there was no difference in Th2 cytokines, such as IL-4 and IL-10. Considered collectively, our results demonstrated that sCD4 could directly prevent host resistance and DTH response to C. neoformans through interference with the production of Th1-type cytokines.

Animals↗
PubMed1998

Involvement of C3a and C5a in interleukin-8 secretion by human polymorphonuclear cells in response to capsular material of Cryptococcus neoformans.

In a previous paper we demonstrated that human polymorphonuclear cells (PMN) in the presence of normal human serum (NHS) secrete proinflammatory cytokines in response to Cryptococcus neoformans or its major capsular component, glucuronoxylomannan (GXM). The hypothesis that activation of the complement system could be responsible for the observed phenomenon is supported by the fact that encapsulated and acapsular C. neoformans isolates are activators of the complement system and, in particular, large encapsulated isolates are powerful activators. In the present study we demonstrate that (i) interleukin-8 (IL-8) release in response to acapsular or encapsulated strains of C. neoformans is significantly reduced in the presence of heat-inactivated serum rather than NHS and is completely abrogated in the absence of human serum; (ii) GXM-induced IL-8 release is strictly dependent on the presence of NHS, is inhibited by specific antibodies to either C3a and C5 complement components, and is completely abrogated by the combined use of these antibodies; (iii) the addition of purified C3a and C5a directly stimulates IL-8 release by PMN; and (iv) monoclonal antibody to GXM in combination with GXM or encapsulated C. neoformans potentiates IL-8 release by PMN. These data shed light on the mechanism involved in GXM-induced IL-8 secretion by PMN, provide an additional potential role for complement in the control of C. neoformans infections, and suggest a complex interplay between the complement system, humoral immunity, and cytokine regulation.

Cells, Cultured↗
PubMed2002

Purification and characterization of a second immunoreactive mannoprotein from Cryptococcus neoformans that stimulates T-Cell responses.

Although T-cell responses are known to be critical for effective host defenses against the fungal pathogen Cryptococcus neoformans, the antigens that stimulate protective responses are poorly characterized but are thought to be comprised, at least in part, of mannoproteins. Recently, we created a panel of murine CD4(+)-T-cell hybridomas that react with C. neoformans antigens. A mannoprotein antigen, MP98, that stimulated one of the hybridomas was purified, and the gene encoding MP98 was cloned. In the present study, the cryptococcal antigen, MP88, that stimulated a second T-cell hybridoma, X5A3, to secrete interleukin-2 was characterized. MP88 was purified from supernatants of glass bead-disrupted C. neoformans by anion-exchange and hydrophobic interaction chromatography. A single band with an apparent molecular mass of 88 kDa was resolved by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and subjected to partial internal amino acid sequencing. The gene encoding MP88 was cloned and sequenced. MP88 features a C-terminal serine/threonine-rich region, which presumably serves as a site for extensive O glycosylation, followed by a putative glycosylphosphatidylinositol anchor site. A search of C. neoformans genomic databases revealed that MP88 shares this feature with at least 11 other genes, including MP98. The mannoprotein nature of MP88 was established based upon the capacity of (i) the mannoprotein fraction of C. neoformans supernatants to stimulate X5A3 and (ii) mannosylated ligands to competitively inhibit this stimulation. Thus, a second cryptococcal mannoprotein has been identified which stimulates T-cell responses and is a vaccine candidate.

Amino Acid Sequence↗
PubMed2001

The Cryptococcus neoformans STE11alpha gene is similar to other fungal mitogen-activated protein kinase kinase kinase (MAPKKK) genes but is mating type specific.

Partial sequence analysis of the Cryptococcus neoformans MATalpha mating type locus revealed the presence of a gene with substantial sequence similarity to other fungal mitogen-activated protein (MAP) kinase kinase kinase (MAPKKK) genes. The C. neoformans gene, designated STE11alpha, showed the highest degree of similarity to the Neurospora crassa nrc-1, Schizosaccharomyces pombe byr2 and Saccharomyces cerevisiae STE11 genes. A polymerase chain reaction-mediated sib-selection technique was successfully adapted for the purpose of disrupting STE11alpha. C. neoformans ste11alphaDelta mutants were found to be sterile, consistent with the phenotypes of ste11 and byr2 mutants in S. cerevisiae and S. pombe respectively. Haploid ste11alphaDelta mutants were also found to be unable to produce hyphae, suggesting that the C. neoformans gene is functionally conserved when compared with its S. cerevisiae MAPKKK counterpart. Comparison of the wild-type STE11alpha strain with a ste11alphaDelta disruptant for virulence using the mouse model showed that the ste11alphaDelta strain was less virulent, but the difference was only minor. In spite of some of the conserved functions of STE11alpha, linkage analysis showed that STE11alpha is only found in mating type alpha strains. These results demonstrate that, although functionally conserved, the mating pathway in C. neoformans has a unique organization.

Amino Acid Sequence↗
PubMed1999

First environmental isolation of Cryptococcus neoformans var. neoformans and var. gatti from the Gharbia Governorate, Egypt.

Flowers from two Eucalyptus camaldulensis trees in the Qutur area and one tree from the Tanta area yielded three isolates of Cryptococcus neoformans var. gattii. Pigeon and sparrow droppings were also investigated for the occurrence of C. neoformans within the study area. Ninety five isolates of the neoformans variety of C. neoformans were recovered from 550 samples of avian droppings.

Animals↗