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PubMed2002

Cryptococcosis in a bottlenose dolphin (Tursiops truncatus) caused by Cryptococcus neoformans var. gattii.

We describe the first case of cryptococcosis caused by Cryptococcus neoformans var. gattii in a male Atlantic bottlenose dolphin (Tursiops truncatus). The dolphin showed clinical signs of tachypnea, transient dyspnea, and mild tachycardia and developed multiple hyperechoic nodules, parenchymal consolidation, and thickening of pleura. A diagnosis of bronchopneumonia with pleuritis was made. Itraconazole therapy was implemented for 120 days, and trough levels in serum were within or above the suggested therapeutic range. Titers of cryptococcal antigen in serum increased eightfold during therapy, and the case had a fatal outcome. Necropsy examination findings included enlarged pulmonary lymph nodes and extensive coalescing granulomatous lesions throughout both lungs. Histologic examination revealed numerous, spherical to ellipsoidal, mucicarmine-positive, 3- to 14-microm, encapsulated, budding cells consistent with C. neoformans. Culture of the lung tissue yielded colonies of C. neoformans. The isolate was urease positive and nitrate negative and exhibited phenoloxidase activity. It was positive on canavanine-glycine-bromothymol blue agar. When tested by the Iatron serodiagnostic reagent kit (Iatron Laboratories, Inc.), it was shown to belong to serotype B.

Animals↗
PubMed1996

IL-12 protects mice against pulmonary and disseminated infection caused by Cryptococcus neoformans.

We examined the role of IL-12 in host resistance to Cryptococcus neoformans using a murine model of pulmonary and disseminated infection. In this model, mice were infected intratracheally with viable yeast cells. Mice untreated with IL-12 allowed an uncontrolled multiplication of yeast cells in the lung with infiltrations of few inflammatory cells, and a cryptococcal dissemination to the brain and meningitis by 3 weeks, resulting in death of all animals within 4-6 weeks. IL-12, when administered from the day of tracheal infection for 7 days, induced a marked infiltration of inflammatory cells, consisting mostly of mononuclear cells, and significantly reduced the number of viable yeast cells in the lung. The treatment suppressed brain dissemination, as shown by a marked reduction of yeast cells in the brain and prevention of meningitis. These effects resulted in a significant increase in the survival rate of infected mice. In contrast, late administration of IL-12 commencing on day 7 after instillation of yeast cells failed to protect the mice against infection with C. neoformans. In further experiments, early administration of IL-12 markedly induced interferon-gamma (IFN-gamma) mRNA in the lungs of infected mice, while no IFN-gamma mRNA was detected without this treatment. Our results indicate that IL-12 is effective when administered in the early period of pulmonary cryptococcal infection.

Animals↗
PubMed2001

The second STE12 homologue of Cryptococcus neoformans is MATa-specific and plays an important role in virulence.

Cryptococcus neoformans STE12alpha, a homologue of Saccharomyces cerevisiae STE12, exists only in MATalpha strains. We identified another STE12 homologue, STE12a, which is MATa specific. As in the case with Deltaste12alpha, the mating efficiency for Deltaste12a was reduced significantly. The Deltaste12a strains surprisingly still mated with Deltaste12alpha strains. In MATalpha strains, STE12a functionally complemented STE12alpha for mating efficacy, haploid fruiting, and regulation of capsule size in the mouse brain. Furthermore, when STE12a was replaced with two copies of STE12alpha, the resulting MATa strain produced hyphae on filament agar. STE12a regulates mRNA levels of several genes that are important for virulence including CNLAC1 and CAP genes. STE12a also modulates enzyme activities of phospholipase and superoxide dismutase. Importantly, deletion of STE12a markedly reduced the virulence in mice, as is the case with STE12alpha. Brain smears of mice infected with the Deltaste12a strain showed yeast cells with a considerable reduction in capsule size compared with those infected with STE12a strains. When the disrupted locus of ste12a was replaced with a wild-type STE12a gene, both in vivo and in vitro mutant phenotypes were reversed. These results suggest that STE12a and STE12alpha have similar functions, and that the mating type of the cells influences the alleles to exert their biological effects. C. neoformans, thus, is the first fungal species that contains a mating-type-specific STE12 homologue in each mating type. Our results demonstrate that mating-type-specific genes are not only important for saprobic reproduction but also play an important role for survival of the organism in host tissue.

Base Sequence↗
PubMed2006

Peroxisome function regulates growth on glucose in the basidiomycete fungus Cryptococcus neoformans.

The function of the peroxisomes was examined in the pathogenic basidiomycete Cryptococcus neoformans. Recent studies reveal the glyoxylate pathway is required for virulence of diverse microbial pathogens of plants and animals. One exception is C. neoformans, in which isocitrate lyase (encoded by ICL1) was previously shown not to be required for virulence, and here this was extended to exclude also a role for malate synthase (encoded by MLS1). The role of peroxisomes, in which the glyoxylate pathway enzymes are localized in many organisms, was examined by mutation of two genes (PEX1 and PEX6) encoding AAA (ATPases associated with various cellular activities)-type proteins required for peroxisome formation. The pex1 and pex6 deletion mutants were unable to localize the fluorescent DsRED-SKL protein to peroxisomal punctate structures, in contrast to wild-type cells. pex1 and pex6 single mutants and a pex1 pex6 double mutant exhibit identical phenotypes, including abolished growth on fatty acids but no growth difference on acetate. Because both icl1 and mls1 mutants are unable to grow on acetate as the sole carbon source, these findings demonstrate that the glyoxylate pathway can function efficiently outside the peroxisome in C. neoformans. The pex1 mutant exhibits wild-type virulence in a murine inhalation model and in an insect host, demonstrating that peroxisomes are not required for virulence under these conditions. An unusual phenotype of the pex1 and pex6 mutants was that they grew poorly with glucose as the carbon source, but nearly wild type with galactose, which suggested impaired hexokinase function and that C. neoformans peroxisomes might function analogously to the glycosomes of the trypanosomid parasites. Deletion of the hexokinase HXK2 gene reduced growth in the presence of glucose and suppressed the growth defect of the pex1 mutant on glucose. The hexokinase 2 protein of C. neoformans contains a predicted peroxisome targeting signal (type 2) motif; however, Hxk2 fused to fluorescent proteins was not localized to peroxisomes. Thus, we hypothesize that glucose or glycolytic metabolites are utilized in the peroxisome by an as yet unidentified enzyme or regulate a pathway required by the fungus in the absence of peroxisomes.

Acetates↗
PubMed2004

Aggregation of Cryptococcus neoformans by surfactant protein D is inhibited by its capsular component glucuronoxylomannan.

Cryptococcus neoformans is an opportunistic pathogen invading the immunocompromised host. Infection starts with the inhalation of acapsular or sparsely encapsulated cells, after which capsule synthesis is initiated. The capsule is the main virulence factor of this yeast-like fungus. Pulmonary surfactant protein D (SP-D) is an important component of the local innate defense system. In the present study, interactions of SP-D with intact C. neoformans cells and their isolated capsular components were investigated. Although encapsulated cryptococci were bound, SP-D showed the highest affinity for acapsular C. neoformans. Only acapsular cryptococci were aggregated by SP-D. Furthermore, the cryptococcal capsular components glucuronoxylomannan (GXM) and mannoprotein 1 (MP1) were bound with relatively high affinity, in contrast to GalXM and MP2. Binding as well as aggregation of acapsular C. neoformans by SP-D could be inhibited by GXM in concentrations that are likely to be present in the lung after infection, suggesting that not only the capsule hampers SP-D function within the innate defense system of the lung but also the secreted capsular component GXM.

Cell Adhesion↗
PubMed1978

Atypical isolate of Cryptococcus neoformans cultured from sputum of a patient with pulmonary cancer and blastomycosis.

Cryptococcus neoformans was isolated repeatedly from a patient with epider-moid carcinoma and pulmonary blastomycosis. The isolate was atypical in that it had only a minute capsule, caused persistent infection but no perceptible disease in mice, and initially appeared not to assimilate trehalose. Only after an incubation of 2 to 3 weeks did utilization of this substrate become apparent.

Aged↗
PubMed2001

Interdependency of interleukin-10 and interleukin-12 in regulation of T-cell differentiation and effector function of monocytes in response to stimulation with Cryptococcus neoformans.

We previously demonstrated that the principal component of capsular material of Cryptococcus neoformans, glucuronoxylomannan (GXM), induces interleukin-10 (IL-10) secretion from human monocytes. Here we report that encapsulation of the yeast with GXM is able to down-regulate interleukin-12 (IL-12) production by monocytes that would normally occur in the absence of encapsulation. This phenomenon appeared to be the result of inhibition of the phagocytic process by encapsulation with GXM as well as of negative signals such as IL-10 secretion produced by interaction of GXM with leukocytes. Decreased secretion of IL-12 correlated with decreased release of gamma interferon (IFN-gamma) from T cells, suggesting a role for encapsulation with GXM in hindering a T helper type 1 (Th1) response. This is supported by the ability of encapsulation with GXM to limit increased expression of B7-1 costimulatory molecules that otherwise might limit IL-10 secretion. Endogenous IL-10 played a critical role in modulatory activity associated with encapsulation with GXM. Blocking IL-10 with monoclonal antibody to IL-10 resulted in increased (i) IL-12 secretion, (ii) IFN-gamma release from T cells, and (iii) killing of C. neoformans by monocytes. These results suggest that encapsulation with GXM limits development of a protective Th1-type response, an inhibitory process in which IL-10 plays a critical role. Scavengers of GXM and/or IL-10 could be useful in a protective Th1-type response in patients with cryptococcosis.

Antigens, CD↗
PubMed1992

Extensive allelic variation in Cryptococcus neoformans.

The orotidine monophosphate pyrophosphorylase (OMPPase) gene locus of the DNA of 13 Cryptococcus neoformans var. neoformans strains, including 10 recent clinical isolates, was studied by using restriction fragment length polymorphisms and nucleotide sequence analysis. The OMPPase locus (URA5) is highly polymorphic, and at least six alleles were identified. The nucleotide sequences of some alleles differed by up to 5%. The majority of the nucleotide polymorphisms in the protein-coding region occurred at the third codon position and were silent. The low frequency of replacement nucleotide substitutions relative to silent nucleotide substitutions implied that there is strong selection against amino acid changes in OMPPase. The allelic variation suggested that there is extensive genomic diversity among C. neoformans clinical isolates from one geographic area. The various alleles are potentially useful markers in the study of the population structure, epidemiology, and pathogenesis of C. neoformans strains.

Alleles↗
PubMed2005

Antifungal susceptibilities of clinical isolates of Candida species, Cryptococcus neoformans, and Aspergillus species from Taiwan: surveillance of multicenter antimicrobial resistance in Taiwan program data from 2003.

The susceptibilities of nonduplicate isolates to six antifungal agents were determined for 391 blood isolates of seven Candida species, 70 clinical isolates (from blood or cerebrospinal fluid) of Cryptococcus neoformans, and 96 clinical isolates of four Aspergillus species, which were collected in seven different hospitals in Taiwan (as part of the 2003 program of the study group Surveillance of Multicenter Antimicrobial Resistance in Taiwan). All isolates of Candida species other than C. glabrata and C. krusei were susceptible to fluconazole. Among the 59 C. glabrata isolates, 16 (27%) were not susceptible to fluconazole, and all were dose-dependently susceptible or resistant to itraconazole. For three (5.1%) C. glabrata isolates, voriconazole MICs were 2 to 4 microg/ml, and for all other Candida species isolates, voriconazole MICs were </=0.5 microg/ml. The proportions of isolates for which amphotericin B MICs were >/=2 microg/ml were 100% (3 isolates) for C. krusei, 11% (23 of 207 isolates) for Candida albicans, 3.0% (2 of 67 isolates) for Candida tropicalis, 20% (12 of 59 isolates) for C. glabrata, and 0% for both Candida parapsilosis and Candida lusitaniae. For three (4%) Cryptococcus neoformans isolates, fluconazole MICs were >/=16 microg/ml, and two (3%) isolates were not inhibited by 1 mug of amphotericin B/ml. For four (4.2%) of the Aspergillus isolates, itraconazole MICs were 8 microg/ml. Aspergillus flavus was less susceptible to amphotericin B, with the MICs at which 50% (1 microg/ml) and 90% (2 microg/ml) nsrsid417869\delrsid7301351 of isolates were inhibited being twofold greater than those for Aspergillus fumigatus and Aspergillus niger. All Aspergillus isolates were inhibited by </=1 microg of voriconazole/ml, including isolates with increased resistance to amphotericin B and itraconazole. This study revealed the emergence in Taiwan of decreased susceptibilities of Candida species to amphotericin B and of C. neoformans to fluconazole and amphotericin B. Voriconazole was the most potent agent against the fungal isolates tested, including fluconazole- and amphotericin B-nonsusceptible strains.

Antifungal Agents↗
PubMed1998

Antifungal pharmacodynamic characteristics of fluconazole and amphotericin B against Cryptococcus neoformans.

The activity of fluconazole and amphotericin B against three isolates of Cryptococcus neoformans was evaluated, with fluconazole and amphotericin B MICs of 2.0-4.0 mg/L and 1.0 mg/L respectively, using time-kill curve methods. Fluconazole was fungistatic against all isolates tested (<99.9% decrease in cfu from initial inoculum). The fungistatic activity of fluconazole was not enhanced by increasing the concentration of antifungal in solution. In contrast, amphotericin B was markedly fungicidal (> or = 99.9% decrease in cfu from initial inoculum). Both the rate and the extent of amphotericin B activity were enhanced when drug concentration was increased.

Amphotericin B↗
PubMed2002

Treatment of experimental nephrosis by culture filtrate of Cryptococcus neoformans var. gattii (CneF).

The therapeutic effect of the culture filtrate of cryptococcus neoformans var. gattii (CneF) was tested in Adriamycin-induced nephropathy. The CneF was administered at different doses (36, 54 and 90 mg/kg based on carbohydrate concentration), one i.p. injection every 72 hours for a total of 10 injections. The treated patient rats showed a significant reduction in proteinuria, plasma cholesterol concentration, BUN and significant increase in urine creatinine levels. Moreover, treatment with CneF significantly reduced number of glomerular leukocytes and decreased the tubular casts. These data suggest that CneF therapy can ameliorate proteinuria, hypercholesterolemia and suppress the progression of glomerular lesions in experimental model of nephrosis.

Animals↗
PubMed1972

Intracellular fate of Cryptococcus neoformans.

Human peripheral leukocytes were found to engulf and kill cells of Cryptococcus neoformans. Fewer encapsulated than nonencapsulated cells met this fate, since cryptococcal capsular polysaccharide inhibited phagocytosis. During 10 to 12 hr of incubation of nonencapsulated cells in human serum, sufficient polysaccharide was produced to inhibit phagocytosis by 50%. The polysaccharide inhibitor was found in the sera of four patients with cryptococcosis, but not on the surfaces of their leukocytes. Additional experiments indicated that serum is not essential for effective phagocytosis. However, normal human serum contains anticryptococcal activity which is not inhibited by capsular material. Preliminary findings indicate that the phagocytic index of a patient with cryptococcosis may be correlated with the severity of his disease.

Animals↗
PubMed2003

Haploid fruiting in Cryptococcus neoformans is not mating type alpha-specific.

Under appropriate conditions, haploid Cryptococcus neoformans cells can undergo a morphological switch from a budding yeast form to develop hyphae and viable basidiospores, which resemble those produced by mating. This process, known as haploid fruiting, was previously thought to occur only in MATalpha strains. We identified two new strains of C. neoformans var. neoformans serotype D that are MATa type and are able to haploid fruit. Further, a MATa reference strain, B-3502, also produced hyphae and fruited after prolonged incubation on filament agar. Over-expression of STE12a dramatically enhanced the ability of all MATa strains tested to filament. Segregation analysis of haploid fruiting ability confirmed that haploid fruiting is not MATalpha-specific. Our results indicate that MATa cells are intrinsically able to haploid fruit and previous observations that they do not were probably biased by the examination of a small number of genetically related isolates that have been maintained in the laboratory for many years.

Cryptococcus neoformans↗
PubMed1989

Isolation of Cryptococcus neoformans from houses of AIDS-associated cryptococcosis patients in Bujumbura (Burundi).

Cryptococcus neoformans var. neoformans, which is responsible for AIDS-associated cryptococcosis in Bujumbura, was isolated in the domestic environment of seven out of 20 patients with AIDS-associated cryptococcosis. The findings prove that in his own domestic environment, the HIV-positive patient in central Africa is frequently exposed to the yeast and these observations lead us to insist on the suitability of carrying out a systematic survey by means of soluble antigens-sensitized latex in every HIV-positive patient. This also proves the importance of a follow-up of the 'cured' patients who easily can be recontaminated after their return home.

Acquired Immunodeficiency Syndrome↗
PubMed1994

[Ecology of Cryptococcus neoformans in central Africa].

Cryptococcosis associated with AIDS is mainly due to Cryptococcus neoformans var. neoformans which is found in saprophytic form in pigeon droppings. This variety has been isolated in Central Africa, particularly in Zaire, Burundi and Rwanda, from dust collected from the houses of patients with cryptococcosis. Several patients confirmed frequent contact with pigeons. Recent studies in Australia demonstrated a link between the yeast and Eucalyptus of the camaldulensis and teriticornis species. These two species were imported to Central Africa from Australia. Examination of 657 Eucalyptus specimens collected in Rwanda did not detect the yeast in any type of tree. This finding casts doubt on the role of Eucalyptus in the ecology of cryptococcosis in Central Africa.

AIDS-Related Opportunistic Infections↗
PubMed1995

Purification and characterization of malate dehydrogenase from Cryptococcus neoformans.

The NAD-dependent malate dehydrogenase (EC 1.1.1.37) was purified from Cryptococcus neoformans, a basidiomycetious yeast that is an opportunistic pathogen of AIDS patients. The purified enzyme was a dimer of 35 kDa subunits that exhibited uncompetitive substrate inhibition by oxalacetate, typical for mitochondrial malate dehydrogenases from other sources. Product inhibition studies indicated an ordered sequential kinetic mechanism, with pyridine dinucleotide being the substrate that binds to the free enzyme form. Unique aspects of this malate dehydrogenase were inhibition by zinc ion, competitive versus malate with Ki of 30 microM, and inhibition by heparin. Heparin inhibition was competitive versus either NAD or malate, with Ki of 0.35 microM. Heparin molecules of nominal molecular weight of 30,000 or 3000 were equally effective inhibitors. A model is presented to explain the high affinity of the enzyme for heparin.

AIDS-Related Opportunistic Infections↗
PubMed1990

Electron cytochemical studies of Cryptococcus neoformans grown on uric acid and related sources of nitrogen.

Cells of Cryptococcus neoformans grown on xanthine or urate as the sole sources of nitrogen produced numerous, single membrane-bound organelles, deemed to be microbodies. Electron images of these structures showed positive cytochemical staining for catalase and alpha-hydroxy acid oxidase, known marker enzyme activities for microbodies. Microbodies in xanthine and urate-grown cells were cytochemically reactive for the presence of the hydrogen peroxide-producing xanthine and urate oxidases. Molybdenum and phosphorus (elements associated with the cofactor common to nitrogen scavenging enzymes) were detected in the substrate-induced microbodies by X-ray dispersive microanalysis. The single limiting membrane of the substrate-induced microbody was stained by a modified Gomori reaction for the presence of alkaline phosphatase, thereby suggesting the participation of this enzymic activity in the events associated with microbody chemistry.

Alkaline Phosphatase↗
PubMed1977

Capsule size of Cryptococcus neoformans: control and relationship to virulence.

Capsule size of five isolates of Cryptococcus neoformans was controlled by cultivation in media containing varying amounts of sugar. High concentrations of sugar (e.g., 16%) suppressed encapsulation whereas low concentrations (e.g., 1%) allowed maximal encapsulation. Suppression of capsule size was attributed at least in part to the increased osmolarity of the medium because a medium with low sugar concentration but having high osmolarity (by virtue of added sodium chloride) also produced cells having small capsules. The extent of control was more marked with certain of the isolates than with others. Mice were intravenously inoculated with cells of a single isolate cultivated so as to have either small or large capsules, and virulence was measured by comparing death rates. Results indicate that virulence after such an inoculation is a constant characteristic of an isolate and is not affected by size of the capsule of the cells in the inoculum.

Cryptococcus↗