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PubMed1998

Molecular epidemiology and antifungal susceptibility of Cryptococcus neoformans isolates from Ugandan AIDS patients.

Little is known of the antifungal susceptibility patterns and molecular epidemiology of Cryptococcus neoformans from tropical regions. We studied 164 clinical isolates of C. neofomans from 120 Ugandan AIDS patients with cryptococcal meningitis by analyzing their electrophoretic karyotypes and antifungal susceptibility profiles. Computer-assisted analysis of karyotype patterns was performed to generate dendrograms. MICs of fluconazole and flucytosine were determined by reference methods. A total of 43 distinguishable DNA types were identified among the 164 isolates. Only 30 patients (25%) were infected with their own unique strain of c. neoformans, whereas 75% of the patients shared their infecting strain with at least one other patient. Among 17 patients with more than one CSF isolate of C. neoformans, sequential isolates were identical or highly related in 12 (71%) and were different in five patients (29%). The isolates were susceptible to both fluconazole and flucytosine and there were no instances in which a stepwise increase in either fluconazole or flucytosine MICs was observed among serial isolates. These findings suggest that the epidemiology of cryptococcal disease in AIDS patients from tropical regions may be somewhat different from that observed in more temperate climates.

Acquired Immunodeficiency Syndrome↗
PubMed2003

Cleavage of human fibronectin and other basement membrane-associated proteins by a Cryptococcus neoformans serine proteinase.

The interaction between the fungal pathogen Cryptococcus neoformans and human fibronectin (HFN) was examined in this study. Polypeptides from cryptococcal whole homogenates and cell wall with molecular masses of 25 and 35 kDa, respectively reacted with HFN. The relevance of the occurrence of these proteins in intact cells was uncertain, since yeast cells from different strains and serotypes of C. neoformans did not significantly adhere to soluble or solid-phased HFN. In contrast, an exocellular proteolytic activity that cleaves HFN was suggested. Degradation of HFN by culture supernatant fluids was demonstrated by Western blotting using a monoclonal anti-HFN antibody. Several fragments of lower molecular weights were observed which reacted with the antibody. Proteolysis was mediated by a serine protease activity, since HFN cleavage was completely inhibited by phenylmethylsulfonyl fluoride (PMSF), aprotinin, and N-tosyl-L-phenylalanyl chloromethylketone (TPCK), but not by inhibitors of metalo, cysteine, or aspartyl proteases. Similar results were obtained when the fluorogenic peptide carbobenzoxy-phenylalanyl-arginyl-7-amido-4-methylcoumarin (CBZ-Phe-Arg-NHmet-C) was used as substrate. The cryptococcal supernatant also cleaved laminin and type IV collagen, as demonstrated by polyacrylamide gel electrophoresis with co-polymerized proteins. The hydrolysis of these proteins was mediated by a single cryptococcal protease with a molecular mass of 75 kDa. The cleavage of key host components of the basement membrane and extracellular matrix by C. neoformans may be a relevant factor in the process of fungal invasion.

Aprotinin↗
PubMed2004

Disruption of CD40/CD40L interaction influences the course of Cryptococcus neoformans infection.

CD40 signaling has been implicated in various pathogenic processes such as chronic inflammatory disease, graft-versus-host disease, autoimmune disease and cancer. We previously demonstrated in an in vitro system that the CD40/CD40L pathway mediates late interleukin (IL) 12 production in response to Cryptococcus neoformans. The purpose of this study was to examine the course of C. neoformans infection in the absence of CD40/CD40L costimulation. We compared infection in mice genetically lacking CD40L (CD40L(-/-)) and in the wild-type counterpart. The animals were injected intratracheally with C. neoformans and monitored for clearance of the organism and the development of cellular immune response. CD40L(-/-) mice exhibited an exacerbation of infection, evaluated as scarce inflammatory response in the lung, that mirrored an increase of fungal burden. This correlated with impairment of nitrite production and antimicrobial activity by macrophages against C. neoformans and unrelated microorganisms such as Candida albicans. Moreover, IL-12 production by splenic macrophages was diminished in CD40L(-/-) mice and interferon-gamma production by CD4 and CD8 T cells was decreased. CD4 T cells retained the ability to express a costimulatory molecule, CTLA-4, but showed a decrease in CD28 expression. This latter molecule is implicated in a positive effect on proliferation, cytokine production and survival of T cells. Collectively these data demonstrate that absence of CD40L correlates with (i) reduced antimicrobial activity of natural effector cells; (ii) reduction of the magnitude of T cell response; and (iii) increase of fungal growth in the brain. These findings suggest that disruption of CD40/CD40L may be deleterious for development of an efficient immune response to C. neoformans and may identify potential molecular targets for novel immunotherapeutic approaches

Animals↗
PubMed1995

CD4 lymphocyte count in HIV-positive persons exposed to Cryptococcus neoformans.

A report is presented on four HIV-positive homosexual men examined after several months of exposure during cleaning of a flat from masses of pigeon droppings heavily colonized by Cryptococcus neoformans. Only one out of the four persons, with a CD4 lymphocyte count of 50/microL, fell sick from systemic cryptococcosis, but not the others, with CD4 lymphocyte counts of 180, 250, and 630/microL, respectively; they remained clinically and mycologically inconspicuous and free from C. neoformans. Open questions in view of the epidemiology of opportunistic pathogens in AIDS are discussed with regard to the CD4 cell count as a parameter indicating a predisposition for cryptococcosis as an airborne AIDS-defining opportunistic infection. This has been confirmed by specific cultural diagnosis of the agent in both the environment and the patient. Already in 1987/88, the probable source of infection had been the subject of epidemiological studies on C. neoformans in Berlin.

AIDS-Related Opportunistic Infections↗
PubMed1996

Cryptococcus neoformans: paradigm for the role of antibody immunity against fungi?

Cryptococcus neoformans is an encapsulated fungus that is a frequent cause of life-threatening infections in patients with AIDS. C. neoformans has many similarities with encapsulated bacteria such as S. pneumoniae and H. influenzae for which antibody immunity is important in protection. However the role of antibody immunity in protection against C. neoformans has been controversial. Experiments with polyclonal sera have produced conflicting evidence for and against the importance of antibody immunity in host defense. Experiments with monoclonal antibodies (mAb) to the C. neoformans capsular polysaccharide (CPS) have revealed the existence of protective, non-protective and disease-enhancing mAbs, suggesting that the divergent results obtained with polyclonal preparations may be a result of relative proportion of protective and non-protective antibodies in immune sera. Administration of protective mAbs can prolong survival, decrease organ fungal burden, and reduce serum polysaccharide antigen. In vitro experiments suggests that protective mAbs modify the course of infection by enhancing effector cell function against C. neoformans. Addition of mAb to antifungal drugs enhances their efficacy against C. neoformans in vivo and in vitro. Human-mouse chimeric antibodies with activity against C. neoformans have been constructed. A highly immunogenic capsular polysaccharide-protein vaccine has been synthesized that elicits protective antibodies in mice. Antibody immunity elicited by conjugate vaccines or provided by passive administration may be useful in the prevention treatment of human cryptococcal infections.

Animals↗
PubMed1995

Virulence factors of Cryptococcus neoformans.

Cryptococcosis is a serious fungal disease in patients with AIDS or other defects in T-cell-mediated host defenses. Cryptococcus neoformans produces several virulence factors, most notably the polysaccharide capsule and phenol oxidase. Molecular studies of cryptococcal virulence factors have contributed to our understanding of the pathobiology of this yeast, and will enable the identification of new targets for antifungal therapy.

Cryptococcus neoformans↗
PubMed2001

Intracellular parasitism of macrophages by Cryptococcus neoformans.

Cryptococcus neoformans, an encapsulated fungal pathogen, causes meningoencephalitis in immunocompromised patients. Recent in vivo studies have demonstrated that C. neoformans is a facultative intracellular pathogen, as was previously suggested by in vitro studies. For survival in macrophages, C. neoformans utilizes a novel strategy for intracellular parasitism that includes the accumulation of intracellular polysaccharide in cytoplasmic vesicles. Confirmation of the fact that C. neoformans is a facultative intracellular pathogen could provide new insights into several poorly understood areas of cryptococcal pathogenesis, including mechanisms for latency and persistence and the lack of efficacy of humoral immunity. The finding that C. neoformans replicates inside macrophages in vitro in a manner similar to that observed in vivo provides an excellent system to dissect the molecular mechanisms responsible for this unique pathogenic strategy.

Animals↗
PubMed2003

Facile syntheses of the hexasaccharide repeating unit of the exopolysaccharide from Cryptococcus neoformans serovar A.

Two hexasaccharides, beta-D-Xylp-(1-->2)-alpha-D-Manp-(1-->3)-[beta-D-Xylp-(1-->2)-]alpha-D-Manp-(1-->3)-[beta-D-GlcpA-(1-->2)-]alpha-D-Manp and beta-D-GlcpA-(1-->2)-alpha-D-Manp-(1-->3)-[beta-D-Xylp-(1-->2)-]alpha-D-Manp-(1-->3)-[beta-D-Xylp-(1-->2)-]alpha-D-Manp, the repeating unit of the exopolysaccharide from Cryptococcus neoformans serovar A, were synthesized as their methyl glycosides in a regio- and stereoselective manner.

Carbohydrate Conformation↗
PubMed1996

Synthesis of a pentasaccharide corresponding to the repeating unit of the exopolysaccharide from Cryptococcus neoformans serovar D.

The assembly of the pentasaccharide repeating unit of the exopolysaccharide from Cryptococcus neoformans serovar D (i.e. 1) is described. The glucuronic acid residue in 1 is introduced as a glucopyranoside and oxidized in a later stage of the synthesis. Thus, iodonium ion-assisted glycosylation of the partially protected methyl mannopyranoside 11 with ethylthio donor 14 gave, after selective deprotection, disaccharide 18. Elongation of the latter with D-glucopyranoside 35 gave trisaccharide 36. Subsequent protective group manipulations yielded the acceptor 37. Condensation of disaccharide donor 31 with trisaccharide acceptor 37 yielded pentasaccharide 38. Protective group manipulations of 38 afforded 42, the glucoside of which was oxidized to yield the corresponding glucuronide 44. Hydrogenolysis of 44 gave the target pentasaccharide 1.

Carbohydrate Sequence↗
PubMed1996

Synthesis of oligosaccharides corresponding to structures found in capsular polysaccharides of Cryptococcus neoformans--II.

Formula 1 depicts a generalized structure of the capsular polysaccharides of four serotypes of the opportunistic microorganism Cryptococcus neoformans, which appears as one of the major infections in the late stages of development of AIDS. Syntheses are now described of two tetrasaccharides with corresponding structures. These are methyl O-alpha-D-mannopyranosyl-(1-->3)-[O-beta-D-xylopyranosyl-(1-->2)] -O-alpha-D-mannopyranosyl-(1-->3)-alpha-D-mannopyranoside and methyl O-alpha-D-mannopyranosyl-(1-->3)-[O-beta-D-glucopyranosyluronic acid-(1-->2)]-O-alpha-D-mannopyranosyl-(1-->3)-alpha-D-mannopyranoside.

Carbohydrate Conformation↗
PubMed2002

CR3 (CD11b/CD18) and CR4 (CD11c/CD18) are involved in complement-independent antibody-mediated phagocytosis of Cryptococcus neoformans.

IgM and IgA to the Cryptococcus neoformans capsular glucuronoxylomannan (GXM) promote complement-independent phagocytosis by macrophages with efficiency comparable to that of IgG1. IgM- and IgA-mediated phagocytosis of C. neoformans was proportional to CR3 expression, inhibited by Abs to CR3 (CD11b/CD18) and CR4 (CD11c/CD18), and dramatically reduced with macrophages of CD18-deficient mice. IgM and IgA promoted ingestion of yeast cells by CHO cells expressing CR3 and CR4. In contrast, IgG1-mediated phagocytosis was only partially inhibited by Abs to CR3 and CR4. Phagocytosis by IgM and IgA but not IgG1 was inhibited by soluble GXM, which binds CD18. Involvement of CR in antibody-mediated complement-independent phagocytosis indicates a new link between innate and adaptive immune systems.

Animals↗
PubMed2003

Ras1 controls pheromone expression and response during mating in Cryptococcus neoformans.

The Cryptococcus neoformans Ras1 signal transduction pathway controls mating, hyphal differentiation, and the ability of this opportunistic human fungal pathogen to grow at elevated temperatures. To further elucidate how Ras1 signals in this organism, the RAS1 gene was disrupted in the congenic serotype D strain background. Genetic epistasis experiments indicated that Ras1 regulates the mating response through the MAP kinase/pheromone response pathway. In fact, Ras1 is required for the transcriptional induction of elements of the pheromone response pathway. However, the ability of C. neoformans Ras1 to allow growth at 37 degrees C is mediated by a separate signaling pathway. Therefore a single Ras protein may differentially activate distinct downstream targets in response to different signals within the same organism. This conserved signaling motif has been coopted in C. neoformans to regulate mating and morphogenesis in addition to being required for its pathogenic potential.

Crosses, Genetic↗
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↗
PubMed2005

Extracellular enzymatic activity and serotype of Cryptococcus neoformans strains isolated from AIDS patients in Brazil.

One hundred and fifty-one Cryptococcus neoformans strains isolated from AIDS patients in Brazil and maintained in the Adolfo Lutz Institute (São Paulo, Brazil) were tested for phospholipase, protease and other extracellular enzymatic activities and their serotypes determined. Production of extracellular phospholipase and protease was tested by the agar plate methods. Determination of extracellular enzyme profile of the strains was performed by using the API-ZYM kit system, which can test 19 different enzymes. The serotypes were determined by cell agglutination using the Crypto-check method. Among the 151 strains, 147 were identified as serotype A and four strains were serotype AD. Production of extracellular phospholipase and protease was extensive and observable at early stages of incubation. All of the tested strains were positive for the production of both enzymes. In the API-ZYM tests, more than 90 % of the 151 tested strains were positive for esterase C4 (No. 3), esterase lipase C8 (No. 4), leucine arylamidase (No. 6), phosphatase acid (No. 11), naphtol-AS-BI-phosphohydrolase (No. 12), alpha-glucosidase (No. 16) and beta-glucosidase (No. 17). Differences in enzymatic activities between the Brazilian strains and strains isolated in other countries were observed. The phospholipase, protease and other enzyme activities may play a role in host tissue invasion by C. neoformans.

AIDS-Related Opportunistic Infections↗
PubMed2005

[Environmental distribution of Cryptococcus neoformans in the department of Cundinamarca-Colombia].

Cryptococcus neoformans is an opportunistic fungal pathogen that could cause infection in patients with immunodeficiency and healthy patients. The AIDS epidemic has shown the importance of studying the ecology and epidemiology of this fungus. The aim of this investigation was to determine if there was a relationship between the environmental distribution of the different varieties of C. neoformans and the climate zones in two transects located in department of Cundinamarca, in Colombia. For the isolation and identification of the yeast, conventional phenotypic methods were used and it was determined the population density (CFU/g of sample) and which was the variety of greater prevalence in each altitudinal rank. A total of 765 samples, from 26 municipalities were collected; of these 146 corresponded to pigeon droppings (Columba livia), 437 to Eucalyptus detritus (Eucalyptus camaldulensis and related species) and 182 to detritus of almond trees (Terminalia cattapa). C. neoformans was isolated from 46% of the studied municipalities, in both transects and the climate zones: warm, temperate and cold. The results indicated that the greater frequency of positive isolations came from the last climate zone (cold). The population density in pigeon excrements oscillated between 50 and 9.2 x 1,000,000, in eucalyptus between 500 and 10 x 1,000,000 and in almond trees was 50 CFU/g. Of 100,000 positive isolations 31% were serotype A, 59% serotype B and 10% serotype C; 96% of the isolates grew to 37 degrees C and all showed capsule. In conclusion, C. neoformans prevails in the three habitats studied but it showed a predilection for the cold thermal floor; the population densities did not allow defining a standard pattern of occurrence.

Altitude↗
PubMed2002

Phenotypic switching in Cryptococcus neoformans.

Cryptococcus neoformans strains exhibit considerable phenotype variability with regards to the capsular polysaccharide, sterol composition of the cell wall, and cell and colony morphology. Phenotypic changes can occur spontaneously during in vitro passage of strains or during chronic infection in vivo and may be associated with differences in virulence. Studies from our laboratory have demonstrated that phenotype variability can be the result of phenotypic switching. Phenotypic switching is defined as a reversible change of an observable colony phenotype that occurs at a frequency above the expected frequency for somatic mutations. This implies that phenotypic switching represents controlled and programmed changes in this pathogenic yeast rather than random mutations. We have shown that a phenotypic switch from a smooth colony phenotype to a mucoid colony phenotype occurs in vitro and in vivo during chronic infection of mice. More importantly we have now demonstrated that the switch is associated with an increase in virulence and a change in the host immune response. Implications of these findings for the pathogenesis of cryptococcosis are discussed.

Cryptococcosis↗
PubMed2002

Metabolites released by Cryptococcus neoformans var. neoformans and var. gattii differentially affect human neutrophil function.

Differences in the ability of Cryptococcus neoformans var. neoformans (CNVN) and var. gattii (CNVG) to establish localized lesions in the lungs of healthy humans remain unexplained. In this study, CNVG infection in a rat model was characterized by early neutrophil invasion into lung tissue, but phagocytosis of cryptococci was not observed. The chemical composition of non-enzymic components secreted by one strain of each variety (heat-inactivated supernatants from CNVN and CNVG, termed vns and vgs, respectively) were compared, using magnetic resonance spectroscopy. Effects on human neutrophil viability and functions at both pH 5.5 and 7.0 were investigated, as the pH of cryptococcomas was found to be 5.4-5.6 in vivo. The supernatants were similar in composition, although metabolites in vns were generally present in higher concentrations. In addition, vgs contained two novel metabolites-acetoin and dihydroxyacetone. Polyphosphate was observed in cells from both varieties and may be a source of extracellular inorganic phosphate. Superoxide production in the presence of phorbol ester was enhanced by treatment with vns and decreased by vgs. At pH 5.5, vns caused high levels of necrosis in neutrophils, as well as increased adhesion/migration through A549 lung epithelial cell monolayers. Individual supernatant components such as polyols, acetoin, dihydroxyacetone, and gamma-aminobutyric acid exhibited both pro- and anti-inflammatory properties. Overall, we found that vgs was potentially less pro-inflammatory than vns. Inhibition of neutrophil function by products of CNVG may promote survival of extracellular organisms, and local multiplication to form cryptococcomas.

Animals↗
PubMed2003

The origin and maintenance of virulence for the human pathogenic fungus Cryptococcus neoformans.

The origin of virulence in environmental fungi that have no requirement for animal hosts in their life cycle is enigmatic. Cryptococcus neoformans is a human pathogenic fungus with virulence factors for mammalian pathogenesis that also contribute to environmental survival. C. neoformans virulence may originate from selection pressures imposed by environmental predators.

Cryptococcosis↗