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PubMed2005

Two glutathione peroxidases in the fungal pathogen Cryptococcus neoformans are expressed in the presence of specific substrates.

Glutathione peroxidases catalyse the reduction of peroxides by reduced glutathione. To determine if these enzymes are important for resistance to oxidative stress and evasion of the innate immune system by the fungal pathogen Cryptococcus neoformans, two glutathione peroxidase homologues, which share 38 % identity, were identified and investigated. In this study, these peroxidases, Gpx1 and Gpx2, their localization, their contribution to total glutathione peroxidase activity, and their importance to the oxidative and nitrosative stress resistance of C. neoformans are described. It is shown that the two glutathione peroxidase genes are differentially expressed in response to stress. While both GPX1 and GPX2 are induced during t-butylhydroperoxide or cumene hydroperoxide stress and repressed during nitric oxide stress, only GPX2 is induced in response to hydrogen peroxide stress. Deletion mutants of each and both of the glutathione peroxidases were generated, and it was found that they are sensitive to various peroxide stresses while showing wild-type resistance to other oxidant stresses, such as superoxide and nitric oxide. While the glutathione peroxidase mutants are slightly sensitive to oxidant killing by macrophages, they exhibit wild-type virulence in a mouse model of cryptococcosis.

Animals↗
PubMed1999

Monoclonal antibody-mediated toxicity in Cryptococcus neoformans infection: mechanism and relationship to antibody isotype.

Antibody reagents represent an alternative for the therapy of human cryptococcosis, and monoclonal antibody 18B7 (IgG1) is a candidate for phase I trial in humans with cryptococcosis. However, antibody administration to mice with established Cryptococcus neoformans infection has been reported to produce acute lethal toxicity (ALT). The present study confirmed this phenomenon and investigated the mechanism of ALT. ALT was associated with hemoconcentration, hypotension, and circulatory collapse; however, toxicity could be prevented by platelet-activating factor inhibitor, rat antibody to Fc receptor, or IgM before IgG1. Significant isotype-specific differences were found in ALT, which can be interpreted as consistent with the hypothesis that there are distinct Fc receptors for murine IgG1 and IgG3. The IgM and IgG3 isotype preference in antibody responses to polysaccharide antigens in mice may translate to a lack of toxicity of antigen-antibody complexes during the course of infections with encapsulated pathogens.

Animals↗
PubMed1998

Fluconazole susceptibility testing of Cryptococcus neoformans: comparison of two broth microdilution methods and clinical correlates among isolates from Ugandan AIDS patients.

We compared the yeast nitrogen base (YNB) broth microdilution method with the National Committee for Clinical Laboratory Standards (NCCLS) M27-A microdilution reference method for measuring the in vitro susceptibility of Cryptococcus neoformans isolates to fluconazole. A total of 149 isolates of C. neoformans var. neoformans from Ugandan AIDS patients was tested by both methods. An overall agreement of 88% between the two microdilution methods was observed. All isolates grew well in both RPMI 1640 and YNB media, and MICs could be read after 48 h of incubation by both methods. The range of fluconazole MICs obtained with the YNB method was broader than that obtained with the NCCLS method. The extended range of MICs provided by the YNB method may be of clinical value, as it appears that the clinical outcome may be better among patients infected with strains inhibited by lower concentrations of fluconazole as determined by the YNB method. The YNB method appears to be a viable option for testing C. neoformans against fluconazole.

AIDS-Related Opportunistic Infections↗
PubMed1977

Cryptococcus neoformans: size range of infectious particles from aerosolized soil.

Although cryptococcosis is characterized as a chronic central nervous system disease, it is generally accepted that the lungs are the primary portal of entry for the etiological agent. Despite this, there is a distinct lack of evidence that viable airborne particles of Cryptococcus neoformans are small enough to reach the alveoli. Two encapsulated strains and one nonencapsulated strain of C. neoformans were inoculated into 250-g quantities of sterile soil. Throughout the 0 to 12 weeks of incubation, this soil was aerosolized in a sealed chamber with a Waring blender. Samples of the resultant dust cloud were taken with an Anderson air sampler from which the numbers and sizes of viable airborne particles were determined. Of the viable organisms aspirated into the air sampler, 15% were 0.65 to 2 micron in diameter. As incubation time in soil increased, the size of the particles decreased, and increased numbers of C. neoformans cells 0.65 to 2 micron in diameter were isolated. The presence of viable cells less than 2 micron in soil aerosols indicated that, under certain conditions in nature, C. neoformans cells exist in sizes that are capable of deep lung deposition.

Aerosols↗
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↗
PubMed1999

Pulmonary surfactant protein A binds to Cryptococcus neoformans without promoting phagocytosis.

BACKGROUND: Evidence is accumulating that the alveolar collecting surfactant protein A (SP-A) plays an important role in the first line of defence against infiltrating pathogenic micro-organisms and viruses. The ability of SP-A to facilitate the binding and uptake of acapsular Cryptococcus neoformans by monocyte-derived macrophages, human alveolar macrophages, monocytes and polymorphonuclear leucocytes was investigated. MATERIALS AND METHODS: Binding, competition and phagocytosis experiments were performed using a flow cytometry technique. RESULTS: SP-A bound to both the acapsular and the encapsulated form of C. neoformans in a concentration-dependent manner. SP-A showed a threefold better binding to the acapsular yeast: this binding was partly calcium dependent and could be inhibited by mannose (ID50 = 3 mmol L-1) and glucose (ID50 = 2.1 mmol L-1) but not by galactose (ID50 = 391 mmol L-1). SP-A did not function as an opsonin in phagocytosis of acapsular C. neoformans for any of the phagocytes studied. CONCLUSION: Our results indicate that SP-A binds in a concentration-dependent manner to both encapsulated and acapsular C. neoformans. Despite SP-A binding to the acapsular C. neoformans, phagocytosis by various phagocytes was not enhanced.

Animals↗
PubMed2007

Correlation of Neo-Sensitabs tablet diffusion assay results on three different agar media with CLSI broth microdilution M27-A2 and disk diffusion M44-A results for testing susceptibilities of Candida spp. and Cryptococcus neoformans to amphotericin B, caspofungin, fluconazole, itraconazole, and voriconazole.

We compared the Neo-Sensitabs tablet assay to both reference M27-A2 broth microdilution and M44-A disk diffusion methods for testing susceptibilities of 110 isolates of Candida spp. and Cryptococcus neoformans to amphotericin B, caspofungin, fluconazole, itraconazole, and voriconazole. Neo-Sensitabs assay inhibition zone diameters in millimeters on three agars (Mueller-Hinton agar supplemented with 2% dextrose and 0.5 microg/ml methylene blue [MGM], Shadomy [SHA], and RPMI 1640 [RPMI, 2% dextrose]) were obtained at 24 to 72 h. The correlation coefficient of Neo-Sensitabs results with MICs was similar to that of the disk method for most of the five agents on MGM (R, 0.80 to 0.89 versus 0.76 to 0.89, respectively). Overall, superior correlation was observed at 24 h for most agents. The exception was amphotericin B (R values of 0.68 and 0.5 for disk and tablet, respectively, at 48 h versus 0.68 and 0.48, respectively, at 24 h). In general, Neo-Sensitabs results were less consistent on SHA and RPMI agars. Although agreement by breakpoint category of Neo-Sensitabs and disk results with CLSI method M27-A2 was also similar on MGM (92.7 to 98.2% versus 95.5 to 100%, respectively), the Neo-Sensitabs method failed to identify two of the six isolates with high amphotericin B MICs. These data suggest the potential value of the Neo-Sensitabs assay for testing at least four of the five agents against yeasts evaluated in the clinical laboratory.

Amphotericin B↗
PubMed1995

Resistant P45051A1 activity in azole antifungal tolerant Cryptococcus neoformans from AIDS patients.

Azole antifungal compounds are important in the treatment of Cryptococcosis, a major cause of mortality in AIDS patients. The target of the azole drugs is P450 mediated sterol 14 alpha-demethylase. We have investigated the P450 system of Cryptococcus neoformans with respect to azole tolerance observed in clinical isolates which were obtained following the failure of fluconazole therapy. The clinical failure was correlated with in vitro tolerance of azole antifungal when compared to wild-type strains. The microsomal P450 system was typical of yeast and fungi and fluconazole tolerance was not associated with defective sterol biosynthesis. The strains had slightly elevated P450 content and slightly reduced azole levels in the cells, but a clear cause for resistance was the increased level of drug needed to inhibit the sterol 14 alpha-demethylase in vitro.

AIDS-Related Opportunistic Infections↗
PubMed2001

Interactions of posaconazole and flucytosine against Cryptococcus neoformans.

A checkerboard methodology, based on standardized methods proposed by the National Committee for Clinical Laboratory Standards for broth microdilution antifungal susceptibility testing, was applied to study the in vitro interactions of flucytosine (FC) and posaconazole (SCH 56592) (FC-SCH) against 15 isolates of Cryptococcus neoformans. Synergy, defined as a fractional inhibitory concentration (FIC) index of <0.50, was observed for 33% of the isolates tested. When synergy was not achieved, there was still a decrease in the MIC of one or both drugs when they were used in combination. Antagonism, defined as a FIC of >4.0, was not observed. The in vitro efficacy of combined therapy was confirmed by quantitative determination of the CFU of C. neoformans 486, an isolate against which the FC-SCH association yielded a synergistic interaction. To investigate the potential beneficial effects of this combination therapy in vivo, we established two experimental murine models of cryptococcosis by intracranial or intravenous injection of cells of C. neoformans 486. At 1 day postinfection, the mice were randomized into different treatment groups. One group each received each drug alone, and one group received the drugs in combination. While combination therapy was not found to be significantly more effective than each single drug in terms of survival, tissue burden experiments confirmed the potentiation of antifungal activity with the combination. Our study demonstrates that SCH and FC combined are significantly more active than either drug alone against C. neoformans in vitro as well in vivo. These findings suggest that this therapeutic approach could be useful in the treatment of cryptococcal infections.

Animals↗
PubMed1995

Early cytokine production in pulmonary Cryptococcus neoformans infections distinguishes susceptible and resistant mice.

A murine pulmonary infection model utilizing intratracheal inoculation of Cryptococcus neoformans was used to analyze cytokines produced in response to opportunistic pathogens acquired via the respiratory tract. The specific question asked was whether early cytokine secretion in lung-associated lymph nodes (LALN) would predict whether this organism would be cleared from the lung. Lung colony-forming units (CFU) were analyzed in two strains of mice over 12 wk, and lung clearance was found to be strain dependent. C.B-17 mice reduced their lung CFU burden between day 7 and day 14 of infection, had significantly higher in lung CFU than C.B-17 mice. The capacity of cells from lungs and LALN to secrete cytokines was significantly different between the strains when assessed at day 7 and day 14 after inoculation. When compared with sensitive C57BL/6 mice 7 days after infection, resistant C.B-17 mice demonstrated (1) increased interferon-gamma secretion by LALN cells in vitro in response to media alone, heat-killed cryptococci, and the T cell mitogen concanavalin A and (2) increased interleukin (IL)-2 secretion by both LALN and lung cells in response to concanavalin A. IL-4 and IL-10 were comparable or undetectable in both mouse strains, whereas IL-5 was significantly higher in all lung cell cultures of C57BL/6 mice. Thus, an early regional Th1 immune response in C.B-17 mice correlated with resistance to the organism, whereas the absence of this response in C57BL/6 mice correlated with susceptibility.

Animals↗
PubMed1984

Growth inhibition of Cryptococcus neoformans by cloned cultured murine macrophages.

Cloned and unselected bone marrow-derived macrophage cell lines were obtained from A/J, AKR/J, BIO.A(5R), CBA/J, DBA/2, HPC, NZW, and [NZB X NZW]F1 mice, and their interactions were studied in vitro with a lightly encapsulated natural serotype A isolate of Cryptococcus neoformans. Growth inhibition of C. neoformans was seen with all of the cell lines, as determined by enumeration of colony-forming units. Inhibition was enhanced by a high concentration (8%) of fresh mouse serum and was the same for serum obtained from AKR/J (C5 deficient) and BIO.A (C5 normal) mice. Macrophage incubation with fresh AKR/J serum which had been absorbed with heat-killed Cryptococcus cells also inhibited C. neoformans growth. Heat-inactivation, EDTA addition or anti-C3 antibody treatment of fresh serum abolished the opsonic activity for C. neoformans, while EGTA addition to fresh serum was without effect on opsonization. In addition, neither IgM nor IgG1 murine monoclonal antibodies specific for C. neoformans enhanced phagocytosis or killing of the yeast by macrophages. These findings are consistent with the interpretation that C3b is an important modulator of interactions between macrophages and C. neoformans.

Animals↗
PubMed2003

Chronic diarrhoea caused by Cryptococcus neoformans in a non-human immunodeficiency virus-infected patient.

A 43-y-old woman with underlying cervix carcinoma stage IIIB, status postirradiation, and diabetes mellitus with tripathy suffered from chronic diarrhoea for more than 6 months. Stool examination showed few white blood cells and red blood cells. Rectal swab cultures disclosed Cryptococcus neoformans in 2 samples obtained 2 weeks apart. The diarrhoea responded to treatment with oral fluconazole for 4 weeks. Repeated rectal swabs revealed no yeast growth. During follow-up for 4 y, she had no problems with diarrhoea. Chronic diarrhoea caused by C. neoformans is rare and clinical suspicion is needed.

Administration, Oral↗
PubMed1995

Involvement of multiple Cryptococcus neoformans strains in a single episode of cryptococcosis and reinfection with novel strains in recurrent infection demonstrated by random amplification of polymorphic DNA and DNA fingerprinting.

We compared the abilities of random amplification of polymorphic DNA and DNA fingerprinting, with oligonucleotide probes, to type five pairs of Cryptococcus neoformans clinical isolates recovered from five separate human immunodeficiency virus-positive patients in London, England. The two techniques had comparable discriminatory abilities when applied to these isolates. A total of eight different isolate types were demonstrated in these patients. No isolate type was observed in more than one patient. Two of the isolate pairs recovered from single episodes of cryptococcosis within 1 day of each other were genotypically indistinguishable by both methods. The other three pairs of isolates were all distinguishable. One of these isolate pairs was obtained from a single episode of cryptococcosis, while the other two were obtained from recurrent infections. These results indicate that multiple strains of C. neoformans may be responsible for a single episode of cryptococcosis and that recurrent infection may occur as a result of reinfection with a novel strain.

Base Sequence↗
PubMed1977

The influence of 5-fluorocytosine on nucleic acid synthesis in Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus.

5-Fluorocytosine (5-FC) has a rapid inhibitory effect on the synthesis of RNA and DNA in the yeast and hyphal form of Candida albicans. 5-FC has a less marked effect on the RNA and DNA content of sensitive strains of Cryptococcus neoformans and has no effect on the nucleic acid content of Aspergillus fumigatus nor of resistant strains of C. albicans and C. neoformans. 5-FC has a slower inhibitory effect on yeast cell number increase and no effect on hyphal length of hyphal phase C. albicans over a 7-h incubation period. Rapidly growing yeasts of C. albicans and C. neoformans decrease in volume and in dry weight per cell. 5-FC prevents this decrease in sensitive strains. These results have been discussed with respect to the known metabolic pathway of 5-FC, the fungistatic and fungicidal action of 5-FC and the development of resistance to 5-FC.

Aspergillus fumigatus↗
PubMed1984

Cryptococcus neoformans: in vivo protection of mice by pretreatment with pyran copolymer.

Synthetic polyanions have been shown to alter host resistance to infection. The anticryptococcal effect of pyran copolymer was assessed in vivo and in vitro. Pretreatment with pyran copolymer significantly extended mean survival in mice lethally infected with Cryptococcus neoformans when compared to untreated animals (p less than 0.01). The anticryptococcal effect of peritoneal exudate cells (PEC) elicited by 10% thioglycollate or pyran copolymer (25 mg/kg) was assessed in vitro. Initial percent phagocytosis of both encapsulated and non-encapsulated isolates of C. neoformans was greatest in the pyran elicited PEC. Significant killing of C. neoformans in vitro was observed only in pyran-activated PEC cultures combined with non-encapsulated cells of C. neoformans, although pyran PEC did inhibit initial growth of phagocytized encapsulated yeast cells. The protection of pyran copolymer pretreated mice from infection with C. neoformans, but the absence of significant killing of encapsulated yeast in vitro suggest a complex mechanism of host defense which may involve an activation of the reticuloendothelial system by pyran copolymer.

Animals↗
PubMed1982

Comparative ocular pathogenicity of Cryptococcus neoformans, Candida glabrata, and Aspergillus fumigatus in the rabbit.

In a previous study, 88% of rabbits with disseminated infection caused by Candida albicans developed ophthalmoscopically visible, hematogenous endophthalmitis (chorioretinitis) over a 2 week period. To determine the incidence of this ocular complication in disseminated infection caused by Cryptococcus neoformans, Candida glabrata, and Aspergillus fumigatus compared with that caused by C. albicans, the first three species of fungi were injected intravenously (between 10(5) and 10(9) organisms per animal) into 36 New Zealand white rabbits. No chorioretinal lesions were seen by indirect ophthalmoscopy over a 2 week period. C. glabrata and A. fumigatus were not cultured from chorioretinas despite positive cultures from brains and kidneys at 1 and 2 weeks. In contrast, C. neoformans was cultured from 12 of 18 chorioretinas. (mean Log10 3.45 colony forming units/gm of tissue) as well as from the brains and kidneys. The less intense inflammatory cell response to C. neoformans compared with that 10 C. albicans seen on histopathologic examination most likely explains the nondetectability of the cryptococcal chorioretinitis by indirect ophthalmoscopy. These data suggest that C. glabrata. A. fumigatus, and possibly C. neoformans have less ocular pathogenicity than C. albicans in rabbits and correlate with the small number of documented human cases of ophthalmoscopically visible hematogenous endophthalmitis caused by fungi other than C. albicans.

Animals↗
PubMed1993

A potent specific inhibitor of 6-phosphogluconate dehydrogenase of Cryptococcus neoformans and of certain other fungal enzymes.

A particular lot of the zwitterionic buffer, 2(N-morpholino) ethane sulfonic acid (MES), contained a contaminant that inhibited a number of fungal NADP-dependent dehydrogenases. Enzymes that were particularly sensitive include 6-phosphogluconate dehydrogenases from Cryptococcus neoformans and Schizophyllum commune and glucose-6-phosphate dehydrogenase from Schizophyllum commune. A number of NADP-dependent dehydrogenases of animal origin were tested and all were completely insensitive to inhibition except for rat liver 6-phosphogluconate dehydrogenase, which was 10-fold less sensitive than the Cryptococcal enzyme. The pattern of inhibition in all cases was linear competitive versus NADP. The inhibitor has been purified and identified as an ethylenesulfonic acid oligomer. This inhibitor holds promise as a model compound for the development of a specific antifungal agent.

Adenosine Monophosphate↗
PubMed1994

Encapsulation of Cryptococcus neoformans regulates fungicidal activity and the antigen presentation process in human alveolar macrophages.

Our previous studies have shown that unstimulated alveolar macrophages (AM) play a predominant role as antigen-presenting cells in Cryptococcus neoformans infections, while the function as effector cells seems to be of minor relevance. The present study focuses on the role of encapsulation of C. neoformans on fungicidal activity and the antigen presentation process of AM. Fungicidal activity in unstimulated AM occurs to a higher degree when the acapsular strain is employed, but this is impaired compared with other natural effectors, such as peripheral blood monocytes (PBM) and polymorphonuclear (PMN) cells. Cryptococcus-laden AM also induce a higher proliferative response in autologous CD4+ lymphocytes when the acapsular strain is used compared with encapsulated yeast. The enhanced blastogenic response is, in part, ascribed to an augmented IL-2 production by T cells. In addition, higher levels of interferon-gamma (IFN-gamma), but not IL-4, are produced by the responding T cells, when the acapsular strain is used compared with the encapsulated yeast. Moreover, IFN-gamma is able to induce fungicidal activity in AM against the encapsulated yeast and augments killing activity of the acapsular strain. This phenomenon is not mediated by nitric oxide production, but is correlated with an enhancement of fungicidal activity of cytoplasmic cationic proteases. We speculate that encapsulation of C. neoformans could down-regulate the development of the immune response mediated by Cryptococcus-laden AM at lung level.

Adult↗