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PubMed2004

Cyclic AMP-dependent protein kinase catalytic subunits have divergent roles in virulence factor production in two varieties of the fungal pathogen Cryptococcus neoformans.

Our earlier findings established that cyclic AMP-dependent protein kinase functions in a signaling cascade that regulates mating and virulence of Cryptococcus neoformans var. grubii (serotype A). Mutants lacking the serotype A protein kinase A (PKA) catalytic subunit Pka1 are unable to mate, fail to produce melanin or capsule, and are avirulent in animal models, whereas mutants lacking the PKA regulatory subunit Pkr1 overproduce capsule and are hypervirulent. Because other mutations have been observed to confer different phenotypes in two diverged varieties of C. neoformans (grubii variety [serotype A] and neoformans variety [serotype D]), we analyzed the functions of the PKA genes in the serotype D neoformans variety. Surprisingly, the Pka1 catalytic subunit was not required for mating, haploid fruiting, or melanin or capsule production of serotype D strains. Here we identify a second PKA catalytic subunit gene, PKA2, that is present in both serotype A and D strains of C. neoformans. The divergent Pka2 catalytic subunit was found to regulate mating, haploid fruiting, and virulence factor production in serotype D strains. In contrast, Pka2 has no role in mating, melanin production, or capsule formation in serotype A strains. Our studies illustrate how different components of signaling pathways can be co-opted and functionally specialized during the evolution of related but distinct varieties or subspecies of a human fungal pathogen.

Alleles↗
PubMed1993

Evaluation of Gen-Probe's Histoplasma capsulatum and Cryptococcus neoformans AccuProbes.

Gen-Probe's DNA probes were evaluated for use in the identification of clinical isolates of Histoplasma capsulatum var. capsulatum and Cryptococcus neoformans. Ninety-five mould-phase fungi were probed, including 41 isolates of H. capsulatum var. capsulatum. Similarly, 98 yeasts, including 42 C. neoformans isolates, were examined by using the C. neoformans DNA probe. In the study, both probes demonstrated 100% specificity and 100% sensitivity. Their use in the clinical laboratory may significantly reduce the time required for definitive identification of fungi.

Cryptococcosis↗
PubMed1995

Structure of the O-deacetylated glucuronoxylomannan from Cryptococcus neoformans serotype C as determined by 2D 1H NMR spectroscopy.

The primary structure of the O-deacetylated capsular glucuronoxylomannan (GXM) isolated from Cryptococcus neoformans serotype C was investigated by 2D NMR spectroscopy. Assignment of the 1H NMR chemical shifts for the polysaccharide was accomplished from the analysis of DQF-COSY, TOCSY, NOESY and/or ROESY spectra of three isolates (298, 34, and 401). These isolates contain the same polysaccharide glycosyl residues but in different proportions. The serotype C GXM consists of two repeating polysaccharide units that have the following structures: [formula: see text] It is not known if these repeating units comprise a single or two separate polymer chains. The relative amounts of the more highly branched octasaccharide 1 in the isolates studied (i.e., approximately 75% in isolate 34, 50% in isolate 298, and 25% in isolate 401) can be used to explain the serological specificity of these isolates with C. neoformans factor sera, as was previously determined by ELISA in this laboratory. The octasaccharide 1 component is the one previously postulated as the structure of the serotype C GXM although definitive placement of the beta-Xyl-(1-->4) residues had previously not been determined. The heptasaccharide 2 component is uniformly found as the repeating unit in the polysaccharide from serotype B isolates. Additionally, GXM 401 was found to contain a small amount of the hexasaccharide repeating unit usually attributed to serotype A GXM.

Acetylation↗
PubMed2006

Cryptococcus neoformans cells in biofilms are less susceptible than planktonic cells to antimicrobial molecules produced by the innate immune system.

The human pathogenic fungus Cryptococcus neoformans can form biofilms on polystyrene plates and medical devices in a process that requires capsular polysaccharide release. Although biofilms are known to be less susceptible to antimicrobial drugs, little is known about their susceptibility to antimicrobial molecules produced by the innate immune system. In this study, we investigated the susceptibility of C. neoformans cells in biofilm and planktonic states to oxidative and nonoxidative antimicrobial molecules produced by phagocytic cells. The effects of various immune effector molecules on the fungal mass, metabolic activity, and architecture of C. neoformans biofilms were measured by colony counts, 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino) carbonyl]-2H-tetrazolium hydroxide reduction, and confocal microscopy, respectively. Biofilms were more resistant than planktonic cells to oxidative stress but remained vulnerable to cationic antimicrobial peptides. However, melanized biofilms were significantly less susceptible to antimicrobial peptides than nonmelanized biofilms. These results suggest that the biofilm phenotype increases resistance against host immune mechanisms, a phenomenon that could contribute to the ability of biofilm-forming microbes to establish persistent infections.

Amino Acid Sequence↗
PubMed1989

Isolation of saprophytic Cryptococcus neoformans from Puerto Rico: distribution and variety.

Until the present decade, no studies had been conducted in Puerto Rico on the saprophytic distribution and variety of Cryptococcus neoformans. Samples (522) of pigeon droppings from 14 western towns were tested for the presence of C. neoformans. The yeast was recovered from 24.7% (129 isolates) of the samples, representing 10 of the 14 towns studied. All environmental isolates were identified as C. neoformans var. neoformans using canavanine-glycine-bromthymol blue (CGB) agar. The yeast was isolated from 79.4% of the samples in one town, Isabela. The average number of yeast cells isolated from sites within this municipality was 5.1 x 10(5) per gram of pigeon droppings. This was 2.6 times the average number of yeast cells of C. neoformans isolated from sites in other towns. In addition, the yeast was isolated from four patients with the acquired immune deficiency syndrome (AIDS), each of whom died of cryptococcal meningitis. Each of these poorly encapsulated isolates was identified as C. neoformans var. neoformans using CGB agar. The results of this investigation demonstrate that C. neoformans var. neoformans is prevalent in Puerto Rico.

Acquired Immunodeficiency Syndrome↗
PubMed1985

Solitary pulmonary nodule due to Cryptococcus neoformans and Mycobacterium tuberculosis.

This report describes a rare combined infection of Cryptococcus neoformans and Mycobacterium tuberculosis that manifested as a solitary pulmonary nodule in a nonimmunocompromised patient. Transthoracic needle aspiration biopsy was initially nondiagnostic, and histopathologic and culture confirmation of the diagnosis was eventually attained after wedge resection of the nodule. An extensive review of the English literature failed to reveal any reported cases of such a combined infection with a similar clinical presentation. The variable morphologic features of C. neoformans in tissue sections and the protean histologic features of pulmonary cryptococcosis can lead to diagnostic difficulties, as illustrated by this case.

Biopsy, Needle↗
PubMed2002

Antibody-mediated protection in murine Cryptococcus neoformans infection is associated with pleotrophic effects on cytokine and leukocyte responses.

Cryptococcus neoformans, an encapsulated yeast, is a common cause of life-threatening meningoencephalitis in immunosuppressed patients. We previously observed that administration of a monoclonal antibody (MAb) to the capsular polysaccharide to mice with pulmonary infection prolonged survival and enhanced granulomatous inflammation without reducing lung CFU. To understand the mechanism of MAb action, we studied leukocyte recruitment and cytokine profiles in lungs of A/JCr mice. B lymphocytes were the predominant cell type in lung infiltrates, comprising 15 to 30% of the leukocytes. Despite alterations in histological appearance, fluorescence-activated cell sorter analysis revealed no significant difference in total numbers of lung leukocytes in MAb-treated mice and controls. Differences in the immune response to C. neoformans between MAb-treated mice and controls included (i) an increase in the percentage of granulocytes among lung leukocytes on day 14, (ii) higher macrophage surface expression of CD86 on day 28, (iii) larger amounts of IL-10 in lung homogenates at day 7, (iv) a trend toward smaller amounts of gamma interferon mRNA and protein on day 7, and (v) a smaller increase in the levels of interleukin-4 mRNA and protein on day 7. Hence, the immune responses to C. neoformans infection in the presence and absence of specific antibody were qualitatively similar, and antibody administration was associated with several subtle quantitative differences in immune response parameters that could translate into enhanced survival. MAb may function partly by down-regulating the inflammatory response and reducing host damage. Our findings demonstrate unexpected complexity in the interaction between specific MAb and other components of the host immune response.

Animals↗
PubMed2001

Experimental infection of almond trees seedlings (Terminalia catappa) with an environmental isolate of Cryptococcus neoformans var. gattii, serotype C.

Recently, our laboratory reported the isolation of Cryptococcus neoformans var. gattii, serotype C for the first time from almond trees (Terminalia catappa) detritus. The aim of the present study was to establish the survival of C. neoformans in almond trees seedlings. Thirty seedlings were infected in the stems and samples were taken and processed at different times and by different techniques. No morphological alterations (macro or microscopic) were observed in the infected plants. However, C. neoformans was found to be viable for at least 100 days after infection. These data constitute our first approach towards the understanding of the yeast interactions with a host-plant.

Journal Article↗
PubMed1991

Killing of Cryptococcus neoformans by human peripheral blood mononuclear cells stimulated in culture.

Since cell-mediated immunity (CMI) is critical for host defenses against the encapsulated fungus Cryptococcus neoformans, the production of human antifungal effector cells as a consequence of the CMI response was investigated. Peripheral blood mononuclear cells (PBMC) were stimulated in culture with killed C. neoformans. Stimulated (but not unstimulated) PBMC killed a subsequent inoculum of live encapsulated organisms, with maximal killing seen after 3-7 days. Killing required the presence of both adherent and nonadherent stimulated PBMC and was enhanced by anticapsular antibody. In contrast, unstimulated PBMC and the adherent fraction of stimulated PBMC killed an isogenic acapsular strain of C. neoformans. These data suggest that the CMI response controls cryptococcosis by eliciting two populations of fungicidal cells acting synergistically. Moreover, capsule, by thwarting the ability of unstimulated PBMC to kill C. neoformans, seems to obligate the host to mount an immune response to generate fungicidal cells.

Cell Division↗
PubMed2002

Complementation of a capsule deficient Cryptococcus neoformans with CAP64 restores virulence in a murine lung infection.

Cryptococcosis is a systemic infection in humans caused by the opportunistic fungal pathogen, Cryptococcus neoformans. The infection usually presents as chronic meningoencephalitis, but infects via the respiratory tract. A polysaccharide capsule is a major virulence factor, which allows the yeast to resist host defenses. However, the essential role of the capsule in allowing it to resist host defenses during the initial lung infection has not been clearly shown. A mutant acapsular C. neoformans strain 602 was complemented with the CAP64 gene to obtain an encapsulated strain, TYCC38-602. TYCC38-602 persisted in the lungs of C.B-17 mice after intratracheal inoculation and disseminated to the brain, whereas the mutant acapsular 602 and the plasmid control transformant CIP3-602 strains grew less readily in the lung and were infrequently detected in the brain. T cell-mediated immunity, developed to the encapsulated organism, was required to control growth within the lungs and had a significant impact on numbers of yeasts detected in the brain. The parent acapsular strain, but not the transformant control, also required T cells for optimal inhibition of growth within the lung, but not for maintaining control of the colony-forming units (cfu) in the brain. In summary, the cryptococcal capsule plays an important role in lung virulence and dissemination to the brain, and intact immunity is required to control lung growth of the encapsulated yeast.

Animals↗
PubMed2006

Virulence profile of strains of Cryptococcus neoformans var. grubii evaluated by experimental infection in BALB/c mice and correlation with exoenzyme activity.

To evaluate the virulence profile of strains of Cryptococcus neoformans var. grubii, 62 strains of this yeast were inoculated into BALB/c mice. It was found that 69 % of the strains were significantly more lethal to the mice and were recovered from a higher percentage (60 %) of the organs compared with the other 31 % of the strains, which were recovered from 35 % of organs tested. Those strains that provoked higher death rates were also recovered from the central nervous system at a higher rate (84 %) than the less lethal strains (32 %). This finding led to an investigation of the factors that enhanced the capacity for neurological infection and death of the animals. The results of this study suggested that environmental strains present different degrees of virulence. The correlation of exoenzyme production before and after inoculation and between the groups of mice indicated that exoenzyme production had no influence on differences in virulence among the strains studied.

Animals↗
PubMed1996

Concordance of clinical and environmental isolates of Cryptococcus neoformans var. gattii by random amplification of polymorphic DNA analysis and PCR fingerprinting.

Sixty-one clinical and forty-nine environmental isolates of Cryptococcus neoformans var. gattii from Australia and the United States were analyzed by random amplification of polymorphic DNA (RAPD), using 12- to 22-mer primers in pairs, and/or PCR fingerprinting with a single primer derived from the microsatellite core sequence of the wild-type phage M13 (5' GAGGGTGGCGGTTCT 3'). Three major genetic profiles were identified by both typing techniques. A single RAPD profile (VGI) predominated among clinical isolates (44 of 48, 92%) and isolates from host eucalypts (45 of 45, 100%) from Australia. Of the 94 Australian isolates, 4 (3 clinical and 1 environmental) were assigned to profile VGII; 2 of these were recovered from patients and one was recovered from plant debris from Western Australia. Only one Australian clinical isolate was assigned to profile VGIII. A different distribution of RAPD profiles (four VGIII, two VGII, and one VGI) was found among four clinical and three environmental isolates from the United States. RAPD profiles of 8 of the 101 isolates studied revealed minor genetic variants, 4 of profile VGI and 4 of profile VGII. Genetic concordance between the majority of clinical and environmental isolates in Australia is consistent with the hypothesis that human disease is acquired from exposure to host eucalypts. Profiles of clinical isolates were independent of body site of infection, and profiles of all isolates were stable over time. Analysis by PCR fingerprinting confirmed the RAPD results. A second RAPD profile (VGII) was associated with infection in southwest Western Australia, where the two host eucalypts do not occur naturally. This raises the possibility of an alternative and as yet unidentified natural habitat of C. neoformans var. gattii. Our results indicate that RAPD analysis is a sensitive and useful method for investigating environmental sources of human infection with this biotype.

Australia↗
PubMed1995

[Isolation of Cryptococcus neoformans from environments (pigeon excreta) in Nagasaki].

Cryptococcosis is one of the serious deep-seated mycoses in immunocompromised patients, especially those with AIDS. Cryptococcus neoformans ordinarily lives in natural environments such as soil and reproduces in pigeon excreta. It spreads in the air and infects human by inhalation. We isolated C. neoformans from pigeon excreta in hospitals, private houses, parks in Nagasaki from October to December in 1994. C. neoformans was isolated from 4 of 8 samples (50%) of pigeon excreta and the isolation rate increased to 80% (4/5) if they were weathered excreta. Two patients with pulmonary cryptococcosis occurred in the last two years in the area where C. neoformans was isolated during that period. Epidemiological studies of clinical isolates and environmental isolates are important to determine its origin of infection and the route of transmission.

Animals↗
PubMed2005

MyD88 and TLR2, but not TLR4, are required for host defense against Cryptococcus neoformans.

We investigated here the potential role of Toll-like receptors (TLR) and the adaptor protein MyD88 in innate immunity responses to Cryptococcus neoformans, a pathogenic encapsulated yeast. Peritoneal macrophages from MyD88(-/-) or TLR2(-/-) mice released significantly less TNF-alpha, compared with wild-type controls, after in vitro stimulation with whole yeasts. In contrast, no differences in TNF-alpha release were noted between macrophages from C3H/HeJ mice, which have a loss of function mutation in TLR4, relative to C3H/HeN controls. When MyD88- or TLR2-deficient mice were infected with low doses of the H99 serotype A strain, all of the control animals, but none of MyD88(-/-) and only 38% of the TLR2(-/-) animals survived, in association with higher fungal burden in the mutant mice. Both MyD88(-/-) and TLR2(-/-) animals showed decreased TNF-alpha, IL-12p40 and/or IFN-gamma expression in various organs during infection. No difference in susceptibility to experimental cryptococcosis was found between C3H/HeJ mice and C3H/HeN controls. In conclusion, our data indicate that TLR2 and MyD88, but not TLR4, critically contribute to anti-cryptococcal defenses through the induction of increased TNF-alpha, IL-12 and IFN-gamma expression.

Adaptor Proteins, Signal Transducing↗
PubMed2004

In vitro and in vivo efficacies of the new triazole albaconazole against Cryptococcus neoformans.

The activity of albaconazole (UR-9825; J. Uriach & Cía. S.A., Barcelona, Spain) was compared to that of fluconazole against 12 isolates of Cryptococcus neoformans in vitro and against 1 isolate in vivo in a rabbit model of cryptococcal meningitis. Albaconazole was 100-fold more potent in vitro than fluconazole on a per-weight basis and was fungicidal at potentially relevant concentrations for two isolates. MICs ranged from </=0.0012 to 1.25 micro g/ml, with the MICs for most isolates being between 0.039 and 0.156 micro g/ml. Isolates were from human immunodeficiency virus (HIV)-infected and non-HIV-infected patients and were of serotypes A, B, and C; and the fluconazole MICs for some of the isolates were elevated. Infected rabbits were treated with either fluconazole or albaconazole at dosages ranging from 5 to 80 mg/kg of body weight/day. The peak concentrations of albaconazole in serum and cerebrospinal fluid (CSF) averaged 4.14 and 0.62 micro g/ml, respectively, in animals receiving 80 mg/kg/day. Comparison of the concentrations in serum and CSF suggested a level of CSF penetration of approximately 15%. Despite limited penetration into the subarachnoid space, at all three doses tested albaconazole was as effective as fluconazole for the treatment of cryptococcal meningitis in rabbits.

Animals↗
PubMed2005

Proven pulmonary cryptococcosis due to capsule-deficient Cryptococcus neoformans does not differ clinically from proven pulmonary cryptococcosis due to capsule-intact Cr. neoformans.

We compared the clinical manifestations, laboratory and radiologic findings, and outcomes of eight patients with proven pulmonary cryptococcosis (PC) caused by capsule-deficient Cryptococcus neoformans with those of six patients with PC caused by capsule-intact Cr. neoformans. The presentations and outcomes did not differ significantly between the groups.

Adult↗
PubMed1996

Interferon-gamma reduces the capacity of human alveolar macrophages to inhibit growth of Cryptococcus neoformans in vitro.

Cytokine stimulation of mouse and rat macrophages has previously been shown to enhance their capacity to phagocytose and inhibit the growth of Cryptococcus neoformans. To extend these observations to primary human macrophages, we investigated the anticryptococcal activity of human alveolar macrophages stimulated with interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), or macrophage-colony stimulating factor (M-CSF). Neither TNF-alpha nor M-CSF had any effect on fungal growth inhibition compared with unstimulated macrophages. Alveolar macrophages stimulated with IFN-gamma demonstrated reduced fungistasis for C. neoformans compared with controls (49% +/- 15% versus 75% +/- 12%; mean % growth inhibition +/- SD, P < 0.001). Confocal laser scanning microscopy was used to assess binding and phagocytosis of yeast. No difference was observed between unstimulated macrophages and macrophages stimulated with any of the cytokines tested. These data suggest that the cytokine regulation of anticryptococcal macrophage functions in humans differs from the rat and mouse. Conclusions drawn from these models may not necessarily be applicable to human cryptococcosis. In particular, the effects of IFN-gamma on the interaction of human alveolar macrophages with C. neoformans was not predicted based on the mouse and rat macrophage responses.

Animals↗
PubMed2006

An ectophosphatase activity in Cryptococcus neoformans.

There is increasing evidence in the literature showing that fungal pathogens express biologically active ectoenzymes. The expression of surface phosphatases at the cell surface of Cryptococcus neoformans, the etiologic agent of cryptococcosis, was evaluated in the present study. Different isolates of C. neoformans express ectophosphatase activity, which is not influenced by capsule size or serotype. The cryptococcal enzyme is an acid phosphatase, inhibited by classic inhibitors of ectophosphatases, including ammonium molybdate and sodium salts of fluoride and orthovanadate. Only the inhibition of enzyme activity caused by sodium orthovanadate has been shown to be irreversible. The cryptococcal ectoenzyme is also inhibited by Zn2+ and inorganic phosphate, the final product of reactions catalyzed by phosphatases. The ectophosphatase from C. neoformans efficiently releases phosphate groups from different phosphorylated amino acids, giving a higher rate of phosphate removal when phosphothreonine is used as a substrate. Yeast cells with irreversibly inhibited ectophosphatases are less capable of adhering to animal epithelial cells than fungi fully expressing enzyme activity, suggesting that ectoenzyme expression can contribute to the pathogenesis of C. neoformans.

Cryptococcus neoformans↗