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PubMed1999

HIV type 1 envelope glycoprotein gp120 induces development of a T helper type 2 response to Cryptococcus neoformans.

OBJECTIVE: To analyse the contribution of HIV type 1 envelope glycoprotein gp120 to regulation of a T-cell response to Cryptococcus neoformans. DESIGN: Monocytes treated with recombinant gp120 and exposed to C. neoformans were used as antigen presenting cells (APC) in coculture with autologous T lymphocytes. METHODS: Costimulatory and major histocompatibility complex class II molecules were evaluated on APC by flow cytometry analysis. T-cell proliferation was determined as 3H thymidine incorporation. Cytokine production was analysed by enzyme-linked immunosorbent assay. RESULTS: gp120 had multiple effects on APC and the T-cell response including: (i) up-regulation of major histocompatibility complex class II antigens on the APC surface resulting from both redistribution of molecules from the intracellular pool and synthesis of new molecules; (ii) up-regulation of B7-2 molecules on the APC surface; (iii) altered T-cell proliferation; and (iv) promotion of interleukin-4 and inhibition of interferon-gamma synthesis and release. CONCLUSIONS: These data indicate that gp120 alters the normal T-cell response to C. neoformans, promoting a T-helper type 2 response. The altered T-cell response produced by gp120 may play an important role in the pathogenesis of cryptococcosis in the patient with AIDS.

Antigens, Fungal↗
PubMed2005

Cryptococcus neoformans peritonitis in a patient with alcoholic cirrhosis: case report and review of the literature.

In the absence of coexisting HIV infection Cryptococcus neoformans is rarely considered in the differential diagnosis of peritonitis that occurs in patients with cirrhosis and ascites. Here, we report on a 39-year-old male, HIV-negative patient with decompensated alcohol toxic liver cirrhosis who developed a lethal intraperitoneal infection with C. neoformans. We reviewed the literature and found an additional 19 cases with culture confirmed cryptococcal peritonitis in combination with liver disease or AIDS. We suggest that awareness of this unusual but lethal entity may lead to earlier diagnosis and proper treatment.

Adult↗
PubMed2005

Sex-specific homeodomain proteins Sxi1alpha and Sxi2a coordinately regulate sexual development in Cryptococcus neoformans.

Homeodomain proteins are central regulators of development in eukaryotes. In fungi, homeodomain proteins have been shown to control cell identity and sexual development. Cryptococcus neoformans is a human fungal pathogen with a defined sexual cycle that produces spores, the suspected infectious particles. Previously, only a single homeodomain regulatory protein involved in sexual development, Sxi1alpha, had been identified. Here we present the discovery of Sxi2a, a predicted but heretofore elusive cell-type-specific homeodomain protein essential for the regulation of sexual development. Our studies reveal that Sxi2a is necessary for proper sexual development and sufficient to drive this development in otherwise haploid alpha cells. We further show that Sxi1alpha and Sxi2a interact with one another and impart similar expression patterns for two key mating genes. The discovery of Sxi2a and its relationship with Sxi1alpha leads to a new model for how the sexual cycle is controlled in C. neoformans, with implications for virulence.

Amino Acid Sequence↗
PubMedDate not supplied

Interaction between Cryptococcus neoformans and alveolar macrophages.

Phagocytosis, oxidative metabolism and phagolysosomal pH of rat alveolar macrophages (AM) were studied at different points of time after challenge with Cryptococcus neoformans. Phagocytosis was evaluated using a fluorescent quenching technique which distinguishes between attached and ingested organisms. The nitroblue tetrazolium (NBT) test was used as an indirect measurement of the oxidative metabolism of the phagocytes. The pH of the phagolysosomes was measured using a cytofluorometric technique. Both the attachment and ingestion of serum opsonized C. neoformans by AM were slow during the first hours of incubation, but were considerable after 24 h. The oxidative metabolism of Am challenged with the yeast was insignificant during the first hour, but reached high levels after 24 h. Most phagolysosomes in AM with ingested cryptococci had a pH < 5.5. Our results indicate that these AM defence mechanisms, although poor during the first hours after exposure to the yeast, are of significance after 24 h. Thus, in the immunocompetent host the AM should prevent the dissemination of C. neoformans from the lungs.

Animals↗
PubMed1994

Therapeutic efficacy of monoclonal antibodies to Cryptococcus neoformans glucuronoxylomannan alone and in combination with amphotericin B.

The therapeutic efficacy of the immunoglobulin G1 (IgG1) monoclonal antibody (MAb) 2H1 to the Cryptococcus neoformans capsular polysaccharide was studied with and without amphotericin B (AmB) in a murine model of intravenous (i.v.) infection. MAb and AmB were administered by intraperitoneal (i.p.) injection after i.v. infection with a C. neoformans serotype D strain. Intraperitoneal administration of MAb 2H1 resulted in rapid distribution to the intravascular compartment, and the half-lives of i.p. and i.v. administered MAb were similar. Administration of MAb 2H1 alone resulted in increased survival, decreased lung fungal burden, and reduced serum glucuronoxylomannan antigen levels when given 2 to 6 h but not 24 h after infection. In vivo, the combination of MAb 2H1 and AmB was more effective at prolonging survival than either agent alone. MAbs of IgM, IgG1, IgG3, and IgA isotypes given 1 day after infection were effective in reducing serum GXM-D levels, with their relative efficacy being IgG1 > IgG3 > IgM > IgA. In vitro, MAb 2H1 was a potent opsonin of C. neoformans and the combination of MAb 2H1 and AmB was more effective than either agent alone in decreasing C. neoformans colony counts in the presence of the murine macrophage cell line J774.16. The results confirm that capsule-binding MAbs can enhance the effect of AmB against C. neoformans and provide support for considering combined therapy in humans.

Amphotericin B↗
PubMedDate not supplied

In vitro susceptibility to antifungal agents of clinical and environmental Cryptococcus neoformans isolated in Southern of Brazil.

The purpose of the present study was to compare the susceptibility to four antifungal agents of 69 Cryptococcus neoformans strains isolated from AIDS patients with that of 13 C. neoformans strains isolated from the environment. Based on the NCCLS M27-A methodology the Minimal Inhibitory Concentrations (MICs) obtained for amphotericin B, itraconazole and ketoconazole were very similar for clinical and environmental isolates. Clinical isolates were less susceptible to fluconazole than environmental isolates. The significance of these findings and aspects concerning the importance, role and difficulties of C. neoformans susceptibility testing are also discussed.

AIDS-Related Opportunistic Infections↗
PubMed2001

Diversity among strains of Cryptococcus neoformans var. gattii as revealed by a sequence analysis of multiple genes and a chemotype analysis of capsular polysaccharide.

We demonstrated the diversity of Cryptococcus neoformans var. gattii strains by a sequence analysis of multiple genes: (i) the intergenic spacer (IGS) 1 and 2 regions of the rRNA gene; (ii) the internal transcribed spacer (ITS) region, including 5.8S of the rRNA gene; (iii) TOP1 (topoisomerase); and (iv) CAP59. In these studies, we compared C. neoformans var. gattii with varieties grubii, and neoformans of C. neoformans. Phylogenetic analysis indicated that both C. neoformans var. grubii and C neoformans var. neoformans are monophyletic, but C. neoformans var. gattii showed polyphyletic. C. neoformans var. gattii can be divided into three phylogenetic groups, I, II, and III, with high bootstrap support. Phylogenetic group I contains serotype B and C strains, and groups II and III include serotype B strains. Because the serotype B strains of C. neoformans var. gattii exhibited more genetic divergence, the serological characteristics and chemotypes of their capsular polysaccharide were further investigated. No remarkable difference among the serotype B strains was found in the reactivities to factor serum 5, which is specific for serotype B. The NMR spectra of the capsular polysaccharide from serotype B strains could be divided into three characteristic patterns, but the chemical shifts were very similar. These results suggested that the serotype B strain of C. neoformans var. gattii has more genetic diversity than the serotype C strain of C. neoformans var. gattii or the varieties grubii and neoformans of C. neoformans, but there was no correlation between genotype and chemotype.

Bacterial Typing Techniques↗
PubMed1999

Specific activated T cells regulate IL-12 production by human monocytes stimulated with Cryptococcus neoformans.

IL-12 production mediated by a T cell-independent and/or T cell-dependent pathway was investigated in human monocytes responding to Cryptococcus neoformans. The data of this study showed that: 1) appreciable levels of IL-12 were observed when freshly isolated monocytes were exposed to acapsular C. neoformans or Candida albicans and secretion occurred within 24-48 h of incubation; 2) monocytes alone were poor producers of IL-12 when stimulated with encapsulated C. neoformans; 3) the presence of specific anti-glucuronoxylomannan mAb favored IL-12 secretion and Fc cross-linking could play a role; 4) monocytes were able to secrete consistent levels of IL-12 when cultured with activated T cells responding to C. neoformans; 5) the maximum secretion of IL-12 was observed at 5-7 days of culture and was strongly regulated by the presence of endogenous IFN-gamma; and 6) the interaction between CD40 on monocytes and CD40 ligand on activated T lymphocytes responding to C. neoformans played a critical role in IL-12 secretion. These data highlight the mechanisms of IL-12 production by human monocytes exposed to C. neoformans, indicating a possible biphasic secretion of IL-12, dependent on the direct effect of fungal insult, and characterized by consistent secretion of IL-12 that is dependent on the interaction of CD40 with the CD40 ligand expressed on activated T cells responding to C. neoformans.

Antibodies, Monoclonal↗
PubMedDate not supplied

Murine monoclonal antibodies recognizing a non-capsular antigen that distinguishes between Cryptococcus neoformans var. neoformans and C. neoformans var. gattii.

A panel of 4 monoclonal antibodies (mabs) of the IgG1 subclass have been made against a cytoplasmic antigen of Cryptococcus neoformans. Mab 4E2 recognized isolates of C. neoformans var. gatti by enzyme-linked immunosorbent assay (ELISA), whilst the other antibodies did not recognize these antigens. By Western blot 4E2 recognized determinants at 110-125, 65-70, 45-50 and 36-38 kDa. Mabs 9E6, 7C7 and 5D9 recognized bands at 36-38 and approximately 30 kDa. All 4 mabs (4E2, 9E6, 7C7 and 5D9) recognized both non-encapsulated and encapsulated isolates of C. neoformans var. neoformans by ELISA, and in addition showed reactivity to only the cytoplasm and cell membrane of yeasts by immunofluorescence. Mab 7C7 recognized antigens of the closely related fungus Trichosporon beigelii by ELISA but did not recognize any other fungal antigens. The other 3 mabs showed no recognition of T. beigelii or any other fungal pathogens tested.

Animals↗
PubMed1993

Fungicidal properties of defensin NP-1 and activity against Cryptococcus neoformans in vitro.

Defensin NP-1, derived from the neutrophils of rabbits, was tested for its fungistatic and fungicidal activity against strains of Cryptococcus neoformans. The MICs for the encapsulated strains tested ranged from 3.75 to 15.0 micrograms of NP-1 per ml. The minimum fungicidal concentrations for these strains were similar to the MICs. An acapsular strain, however, had a lower MIC of 0.93 and minimum fungicidal concentration of 1.88 micrograms/ml. NP-1 demonstrated time-dependent and concentration-dependent killing of C. neoformans. Killing occurred rapidly in the first 20 min of exposure to NP-1 and was maximum at 90 to 120 min. Killing of C. neoformans by NP-1 was concentration dependent with 31% +/- 9% survival at 25 micrograms/ml, 13% +/- 4% survival at 50 micrograms/ml, 9% +/- 5% survival at 75 micrograms/ml, and 5% +/- 3% survival at 100 micrograms/ml. NP-1's fungicidal effect on C. neoformans was also inoculum dependent, with increased activity observed at 10(4) versus 10(5) or 10(6) cells per ml. In addition, stationary-phase C. neoformans was less susceptible to NP-1 killing than yeast cells in the logarithmic phase. Subinhibitory concentrations of both NP-1 (0.25 x MIC) and fluconazole (0.25 x MIC) acted synergistically in inhibiting growth of C. neoformans. Similar combinations of NP-1 and amphotericin B, however, did not yield synergy.

Amphotericin B↗
PubMedDate not supplied

[Pigmentation of Cryptococcus neoformans strains on sunflower seed agar].

The production of melanin on a medium of sunflower seeds extract agar from 86 strains of Cryptococcus neoformans belonging to the Mycology Laboratory of "Pedro Kouri" Institute of Tropical Medicine was determined. 54.7% of them produced colonies with dark brown pigment, 5.8% a light pigment and 37.2% an intermediate tonality. A fourth group was created for those strains with a true pigment (2.3%). This paper is an important contribution to attain a better characterization of the strains from the collection of the institution and serves as a basis to further studies of pathogenicity and susceptibility.

Agar↗
PubMed1999

Biochemical and functional characterisation of secreted phospholipase activities from Cryptococcus neoformans in their naturally occurring state.

A recent study demonstrated that phospholipase B (PLB), lysophospholipase (LPL) and lysophopholipase transacylase (LPTA) are secreted by Cryptococcus neoformans var. neoformans and showed that the amount of enzyme production correlated with virulence in mice. The present study characterised the extracellular enzyme activities further by radiometric assays and 31P nuclear magnetic resonance spectroscopy (NMR). All three enzymes were most active between 25 and 40 degrees C. Bovine lung surfactant and its major lipid components, disaturated phosphatidylcholine and phosphatidylglycerol, were the optimal substrates for PLB. Lysophosphatidylcholine was the favoured substrate for LPL and LPTA. PLB and LPL/LPTA were differentially affected by Triton X-100, and palmitoyl carnitine was a potent inhibitor of the three phospholipases. LPL and PLB activities were inhibited by dithiothreitol; N-ethylmaleimide inhibited LPL and LPTA activities. None of the enzymes was inhibited by N-bromosuccinimide or p-bromophenacyl bromide. Cellular disruption experiments indicated that >85% of the phospholipase activities were cell-associated, with LPL and LPTA being more easily released than PLB. At pH 5.5 and 7.0, the heat-inactivated secreted enzyme preparations decreased the viability of human neutrophils. This effect was attenuated by active supernates. The relative activities of the PLB, LPL and LPTA in the environment of neutrophils are likely to determine the fate of these cells in vivo. Both phospholipases and heat-stable substances secreted by C. neoformans at 37 degrees C could contribute to membrane degradation and virulence.

Cell Survival↗
PubMed2006

Improvements to gene deletion in the fungal pathogen Cryptococcus neoformans: absence of Ku proteins increases homologous recombination, and co-transformation of independent DNA molecules allows rapid complementation of deletion phenotypes.

Cryptococcus neoformans is a pathogenic fungus that is relatively amenable to molecular genetic analysis, including gene deletion. However, rates of homologous recombination can be low, so obtaining specific gene deletion transformants is challenging. We have utilized two new technologies, cku deletion strains to improve the efficiency of gene deletions in this organism, and co-transformations. The Ku70-Ku80 heterodimer is predicted to be an essential part of the non-homologous end-joining process in C. neoformans. Here we show that a deletion in one or both of these proteins results in an increase in the rates of homologous recombination. Importantly, we demonstrate that after generation of a strain with a particular deletion of interest, the cku deletion can be removed by mating and segregation. We also utilize co-transformation of wild-type genes and selectable markers on separate linear DNA molecules to complement a deletion event. We show that co-transformation results in the successful restoration of wild-type phenotype, though variations in this phenotype often occur.

Animals↗
PubMed1997

Different susceptibility of three clinically isolated strains of Cryptococcus neoformans to the fungicidal effects of reactive nitrogen and oxygen intermediates: possible relationships with virulence.

We investigated the susceptibility of three clinically isolated strains of Cryptococcus neoformans with different virulences to reactive nitrogen and oxygen intermediates (RNI and ROI, respectively), representing two important mediators of macrophage microbicidal activity. All mice infected with the highly virulent strain of C. neoformans, YC-11, died within 3 to 6 weeks because of rapid multiplication of the organism in the lungs and dissemination to the brain. In contrast, a weakly virulent strain, YC-13, was almost completely eradicated from the lungs and did not disseminate to the brain, leading to survival of all infected animals during the period of observation (15 weeks). The virulence of the third strain, YC-5, was intermediate between the other two strains. To examine the susceptibility of C. neoformans to the fungicidal effect of nitric oxide (NO) and superoxide anions (O2-), the organisms were exposed to these oxidants, which were chemically generated in a cell-free system. Interestingly, the number of live YC-13 yeast cells was markedly reduced after exposure to NO and O2-. In contrast, YC-11 was almost completely resistant to the killing effect of these oxidants. YC-5 showed an intermediate susceptibility. Our results demonstrate that the resistance of C. neoformans to the fungicidal effects of RNI and ROI is related to virulence, and suggest that the resistance to nitrogen- and oxygen-derived oxidants may be one of the factors to determine the outcome of infection with C. neoformans.

Animals↗
PubMedDate not supplied

Cryptococcus neoformans var. gattii infection in northern Australia: existence of an environmental source other than known host eucalypts.

The 2 known host trees of Cryptococcus neoformans var. gattii, Eucalyptus camaldulensis and E. tereticornis, do not occur naturally in the 'Top End' of the Northern Territory (NT) of Australia. Nine clinical isolates of C. neoformans var. gattii from the NT were analysed by random amplification of polymorphic deoxyribonucleic acid (RAPD) and polymerase chain reaction 'fingerprinting'. Two isolates were assigned to RAPD profile VGI, previously established as the common RAPD profile. The remaining 7 were assigned to profile VGII; 6 of these isolates were recovered from individuals living in the 'Top End'. The results strongly support the existence of an alternative environmental niche for C. neoformans var. gattii, as all isolates from Eucalyptus spp. in Australia to date have been of RAPD profile VGI.

Cryptococcosis↗
PubMed1993

Phenotypic and functional characterization of human lymphocytes activated by interleukin-2 to directly inhibit growth of Cryptococcus neoformans in vitro.

Recently we demonstrated that the nonadherent (to plastic) fraction of human PBMC could be activated by IL-2 to inhibit Cryptococcus neoformans growth. Here we characterize the antifungal effector cells. Depletion by panning of natural killer (NK) (CD16+, CD56+) cells from nylon wool-treated, IL-2-activated PBMC markedly decreased lytic activity against a tumor cell target (K562) but did not affect antifungal activity. Panning out T (CD3+, CD5+) cells enhanced activity against tumor cells but partially abrogated activity against C. neoformans. IL-2-activated T cells of 95% purity, obtained by panning out NK cells from PBMC forming rosettes with sheep erythrocytes, had excellent antifungal activity but suboptimal antitumor activity. The nonrosetted cells (which were virtually free of T cells and enriched for NK cells) had both antitumor and antifungal activity, even if cultured without IL-2. CD4+, CD8+, and CD56+ cells, purified by positive selection by panning, directly inhibited cryptococcal growth. Conjugate formation between fungi and both CD56+ and CD5+ effector cells was demonstrated by videomicroscopy and immunoperoxidase staining. Thus, IL-2-activated T cells and NK cells form conjugates with and directly inhibit the growth of C. neoformans. To our knowledge, these data are the first demonstration of human T cells directly inhibiting growth of a microbial target.

Animals↗
PubMed1996

Capsular polysaccharide of Cryptococcus neoformans induces proinflammatory cytokine release by human neutrophils.

Human polymorphonuclear leukocytes from normal subjects produced proinflammatory cytokines in response to stimulation with Cryptococcus neoformans yeast cells. The cytokines released after stimulation of neutrophils included interleukin-1beta (IL-1beta), IL-6, IL-8 and tumor necrosis factor alpha. The magnitude of the cytokine response was related to the yeast capsule size. Cells of a large-capsule isolate stimulated release of greater amounts of cytokine than did a thinly encapsulated isolate, which, in turn, stimulated release of greater amounts of cytokine than an acapsular isolate. Cytokine release was also stimulated by supernatant fluids from cryptococcal cells that were preincubated with 10% human serum, suggesting the generation of a soluble mediator. The major capsular polysaccharide, glucuronoxylomannan, stimulated release of tumor necrosis factor alpha, IL-1beta, and IL-8 in a dose-dependent fashion. These results differ from previous studies of cytokine secretion by human monocytes in several important respects, including the importance of encapsulation in stimulation of cytokine secretion and the ability of purified glucuronoxylomannan to induce cytokine secretion.

Cryptococcus neoformans↗