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PubMed1990

Periorbital necrotising fasciitis due to Cryptococcus neoformans in a healthy young man.

A case report is presented of a healthy 25-year-old man who developed a periorbital necrotising fasciitis after a trivial trauma with a wooden splinter. Necrotising fasciitis of the eyelids occurs rarely. Cryptococcus neoformans is not described as a causative factor of necrotizing fasciitis. Cryptococcus neoformans usually infects patients with immunodeficiencies, diabetes mellitus or steroid therapy. This patient was healthy and developed a periorbital necrotising fasciitis due to Cryptococcus neoformans.

Adult↗
PubMed1984

Resistance to challenge and macrophage activity in mice previously vaccinated with formalin-killed Cryptococcus neoformans.

Mice were vaccinated with formalin-killed Cryptococcus neoformans either intranasally, intravenously, or intraperitoneally. Resistance to lethal challenge and in vitro phagocytic activity of alveolar and peritoneal macrophages was studied. Increased resistance to lethal challenge was seen following vaccination by each of the three routes but increased phagocytic activity was seen only in alveolar macrophages from mice vaccinated intranasally.

Administration, Intranasal↗
PubMed1992

Use of a dispersed repetitive DNA element to distinguish clinical isolates of Cryptococcus neoformans.

We isolated a recombinant phage from a Cryptococcus neoformans genomic library that contains a member of a dispersed family of repetitive DNA elements. This clone, CNRE-1, hybridized to at least seven chromosomes in C. neoformans on the basis of pulsed-field gel analysis. Hybridization of CNRE-1 to restriction digests of genomic DNA confirmed that there are multiple copies of this element and that restriction fragment length polymorphisms are present in strains from different serotypes of C. neoformans. The utility of this probe as an epidemiologic marker was determined by testing cryptococcal isolates from a single hospital. Five isolates from four patients were closely related to a serotype A reference strain, whereas five other isolates from four additional patients exhibited distinct patterns. In two patients, the isolates obtained during recurrent cryptococcal infections were identical to the original isolates.

Acquired Immunodeficiency Syndrome↗
PubMed2000

Postantifungal effects of echinocandin, azole, and polyene antifungal agents against Candida albicans and Cryptococcus neoformans.

The postantifungal effect (PAFE) of fluconazole, MK-0991, LY303366, and amphotericin B was determined against isolates of Candida albicans and Cryptococcus neoformans. Concentrations ranging from 0. 125 to 4 times the MIC were tested following exposure to the antifungal for 0.25 to 1 h. Combinations of azole and echinocandin antifungals (MK-0991 and LY303366) were tested against C. neoformans. Fluconazole displayed no measurable PAFE against Candida albicans or Cryptococcus neoformans, either alone or in combination with either echinocandin antifungal. MK-0991, LY303366, and amphotericin B displayed a prolonged PAFE of greater than 12 h against Candida spp. when tested at concentrations above the MIC for the organism and 0 to 2 h when tested at concentrations below the MIC for the organism.

Amphotericin B↗
PubMed2005

Cryptococcus neoformans peritonitis in two patients with liver cirrhosis.

Cryptococcus neoformans is an important pathogen in immunocompromised patients. We report 2 cases of spontaneous C. neoformans peritonitis in patients with liver cirrhosis, a condition not previously reported in Taiwan. Patient 1, a 59-year-old man with alcoholic liver cirrhosis, had primary C. neoformans peritonitis with fungemia. The patient recovered completely after prolonged fluconazole therapy without relapse. Patient 2, a 51-year-old woman with liver cirrhosis due to Budd-Chiari syndrome, had C. neoformans isolated from ascites, cerebrospinal fluid, and blood culture. In spite of adequate antifungal treatment, the patient died of fulminant sepsis. Information about the interaction and relation between liver cirrhosis and cryptococcal peritonitis is rare in the literature. The experience of these cases may help facilitate the diagnosis and treatment of cryptococcal peritonitis.

Cryptococcosis↗
PubMedDate not supplied

[Cryptococcosis. A study of 9 strains of Cryptococcus neoformans isolated from immunodeficient patients].

Five strains of Cryptococcus neoformans isolated from the cerebro-spinal fluid and 4 from the blood of AIDS patients, were studied. Although morphologically identical, they differed in the auxanographic pattern. All strains were pathogenic for mice by intracerebral route. Six isolates were sensitive and the other three resistant to 5-fluorocytosine. All strains were sensitive to the other antifungal tested: nystatin, amphotericin B, clotrimazole, miconazole, econazole and ketoconazole.

Acquired Immunodeficiency Syndrome↗
PubMed2004

Involvement of CD14, toll-like receptors 2 and 4, and MyD88 in the host response to the fungal pathogen Cryptococcus neoformans in vivo.

The major capsular polysaccharide of Cryptococcus neoformans, glucuronoxylomannan (GXM), is recognized by Toll-like receptor 2 (TLR2), TLR4, and CD14. In these studies, mice deficient in CD14, TLR2, TLR4, and the TLR-associated adaptor protein, MyD88, were utilized to investigate the contribution of TLRs and CD14 to in vivo host defenses against C. neoformans. MyD88(-/-) mice had significantly reduced survival compared with wild-type C57BL/6 mice after intranasal (i.n.) and intravenous (i.v.) infection with live C. neoformans. CD14(-/-) mice had reduced survival when infected i.v., while TLR2(-/-) mice died significantly earlier after i.n. infection. Mortality was similar comparing TLR4 mutant C3H/HeJ mice and control C3H/HeOuJ mice following i.v. or i.n. challenge with C. neoformans. The course of pulmonary cryptococcosis was studied in more detail in the CD14(-/-), TLR2(-/-), and MyD88(-/-) mice. MyD88(-/-) mice infected i.n. had higher numbers of CFU in the lungs as well as higher GXM levels in the sera and lungs 7 days after infection than wild-type mice did. Surprisingly, there were no major differences in the levels of tumor necrosis factor alpha, interleukin-4 (IL-4), IL-10, IL-12p70, or gamma interferon in the lungs of C. neoformans-infected knockout mice compared with wild-type mice. Histopathologic analysis of the lungs on day 7 postinfection revealed minimal inflammation in all mouse groups. These studies demonstrate a major role for MyD88 and relatively minor roles for CD14 and TLR2 in the response to cryptococcal infection, with the decreased survival of MyD88(-/-) mice correlating with increased numbers of lung CFU and serum and lung GXM levels.

Adaptor Proteins, Signal Transducing↗
PubMed1996

Preclinical efficacy of a glucuronoxylomannan-tetanus toxoid conjugate vaccine of Cryptococcus neoformans in a murine model.

The encapsulated yeast, Cryptococcus neoformans, causes life-threatening meningoencephalitis in immunocompromised humans, especially in AIDS patients. Fatality and relapse rates remain quite high despite aggressive therapy. A conjugate vaccine composed of the cryptococcal capsular glucuronoxylomannan covalently coupled to tetanus toxoid (GXM-TT) was constructed and evaluated. The vaccine elicited high levels of capsular antibodies in mice by active and passive immunizations and conferred 70-80% protection against a moderate challenge with 10(3) C, neoformans. Monitoring of serum GXM and anti-GXM antibody levels and of incidence of cryptococcal isolation from various organs of mice suggested that presence of vaccine-induced antibodies during the first 4-6 weeks of infection is critical for clearance of cryptococci from various organs, for limiting serum GXM titers from reaching immunosuppressive levels and ultimately for survival. GXM-TT is the first defined fungal vaccine to confer antibody-mediated protection against a systemic mycosis in an animal model. GXM-TT is being evaluated for safety and immunogenicity in healthy and HIV-infected human volunteers at the National Institutes of Health.

Animals↗
PubMed2000

Timed-kill curves for Cryptococcus neoformans isolated from patients with AIDS.

Infection with Cryptococcus neoformans is an increasing problem in immunocompromised patients, particularly those with acquired immune deficiency syndrome (AIDS). Amphotericin B and fluconazole are currently acceptable therapies for cryptococcal meningitis; however, their effects remain suboptimal and recurrence or treatment failure is still a problem. Antifungal susceptibility testing may be an important tool for guiding therapy, but for C. neoformans, a reliable method is still not available. This retrospective study evaluated minimal inhibitory concentration (MIC) for amphotericin B and fluconazole, and minimal fungicidal concentration (MFC) and timed-kill curves for amphotericin B against 16 clinical isolates of C. neoformans obtained from AIDS patients with cryptococcal meningitis. No correlation between clinical outcome and MIC was observed for amphotericin B. In selected cases, the MFC seemed to be a better predictor of outcome than MIC. In this study, amphotericin B timed-kill curves appeared to show a correlation with clinical outcome of the 16 patients with AIDS-associated cryptococcal meningitis. These in vitro tests must be further evaluated in prospective studies to confirm their potential usefulness for guiding cryptococcal meningitis therapy.

AIDS-Related Opportunistic Infections↗
PubMed2003

Cloning of CnLYSO1, a novel extracellular lysophospholipase of the pathogenic fungus Cryptococcus neoformans.

We cloned a novel lysophospholipase (CnLYSO1) from Cryptococcus neoformans var. grubii by PCR amplification and a cDNA library screen. The open reading frame (ORF) of 1278 nucleotides coded for a predicted 426-amino-acid protein (CnLyso1p) with two highly conserved GXSXG lipase-specific catalytic motifs and a molecular weight of 48.3 kDa. CnLyso1p exhibited 14% and 21% identity to Arabidopsis thaliana and human lysophospholipases, respectively. Immunoprecipitation and Western blot analyses indicated that CnLyso1p was secreted as a high molecular weight protein of 97-140 kDa. CnLYSO1 expressed in a phospholipase B-null mutant of Saccharomyces cerevisiae demonstrated lysophospholipase and lysophospholipase transacylase activities at pH 4.0. Targeted disruption of CnLYSO1 did not affect growth, melanin or capsule production by C. neoformans. Secreted lysophospholipase and transacylase activities (pH 4.0) were 50% of wild type and CnLyso1p was undetectable on Western blots. Phospholipase B activity was reduced at pH 7.0 (P<0.006) and at pH 4.0 (P=NS). The amount of secreted Plb1p (the gene product of PLB1) was also reduced. Deletion of PLB1 abolished all three secreted activities at pH 4.0 and 7.0. These results are best explained by post-translational interaction, most likely the formation of a functional complex between the independently regulated gene products, CnLyso1p and CnPlb1p.

Amino Acid Sequence↗
PubMed2003

Antibodies to keyhole limpet hemocyanin cross-react with an epitope on the polysaccharide capsule of Cryptococcus neoformans and other carbohydrates: implications for vaccine development.

Cryptococcus neoformans causes a life-threatening meningoencephalitis in AIDS patients. Mice immunized with a glycoconjugate vaccine composed of the glucuronoxylomannan (GXM) component of the cryptococcal capsular polysaccharide conjugated to tetanus toxoid produce Abs that can be either protective or nonprotective. Because nonprotective Abs block the efficacy of protective Abs, an effective vaccine must focus the Ab response on a protective epitope. Mice immunized with peptide mimetics of GXM conjugated to keyhole limpet hemocyanin (KLH) with glutaraldehyde developed Abs to GXM. However, control peptides P315 and P24 conjugated to KLH also elicited Abs to GXM. GXM-binding Abs from mice immunized with P315-KLH were inhibited by KLH treated with glutaraldehyde (KLH-g), but not by P315. Furthermore, KLH-g inhibited binding of GXM by serum of mice immunized with GXM-TT, indicating that glutaraldehyde treatment of KLH reveals an epitope(s) that cross-reacts with GXM. Vaccination with KLH-g or unmodified KLH elicited Abs to GXM, but did not confer protection against C. neoformans, suggesting the cross-reactive epitope on KLH was not protective. This was supported by the finding that 4H3, a nonprotective mAb, cross-reacted strongly with KLH-g. Sera from mice immunized with either native KLH or KLH-g cross-reacted with several other carbohydrate Ags, many of which have been conjugated to KLH for vaccine development. This study illustrates how mAbs can be used to determine the efficacy of potential vaccines, in addition to describing the complexity of using KLH and glutaraldehyde in the development of vaccines to carbohydrate Ags.

Amino Acid Sequence↗
PubMed2006

Isolation of Cryptococcus neoformans var. neoformans serotype D from Eucalypts in South Brazil.

Cryptococcus neoformans causes the second most common opportunistic infection in patients with AIDS. In Brazil, 4.5% of the AIDS-related opportunistic infections are caused by C. neoformans and all varieties are recognized as etiological agents of cryptococcosis. This pathogen is a ubiquitous environmental yeast, commonly associated with avian excreta and decaying wood, especially Eucalypt species. The aim of the present study was to search for C. neoformans in Eucalypts and analyze the genotypic diversity of the obtained isolates by RAPD and PCR fingerprinting. All obtained isolates have been C. neoformans var. neoformans, serotype D molecular type VNIV. Serotype D, was isolated from 3 (37.5%) out of 8 cities surveyed in the South Brazilian state Rio Grande do Sul. Nine (9%) out of 99 environmental samples were obtained from Eucalypt species, Eucalyptus calmadulensis and Eucalyptus tereticornis. Molecular analysis using RAPD and PCR-fingerprinting revealed very little genetic diversity in the obtained cryptococcal serotype D isolates. To our knowledge this is the first report of the isolation of serotype D from Eucalyptus trees in Brazil. More studies are required in order to establish the ecological significance of this finding.

Brazil↗
PubMed1996

Structure of the O-deacetylated glucuronoxylomannan from Cryptococcus neoformans Cap70 as determined by 2D NMR spectroscopy.

Cryptococcus neoformans, an opportunistic pathogen, is the fourth leading cause of death among AIDS patients. The yeast's capsule is a major virulence factor, and serotype is related to the chemical structure of glucuronoxylomannan (GXM), its capsular polysaccharide. The GXM from Cap70, a hypocapsular mutant of serotype D isolate B-3501, was investigated by chemical analysis and 2D NMR spectroscopy. The assignment of 1H and 13C chemical shifts for the O-deacetylated polysaccharide was accomplished from the analysis of DQF-COSY, TOCSY, and gradient-enhanced HSQC spectra. The sequence and linkage positions of glycosyl residues were determined by NOESY and ROESY spectra. Two repeating polysaccharide components were identified as having the following structures in approximately equal proportions: [formula: see text] It is not known if these repeating units comprise a single or two separate polymer chains. Pentasaccharide 2 has been known to be the major GXM polymer of B-3501 and other serotype D isolates. Hexasaccharide 1 is identified for the first time although it has subsequently been identified in other C. neoformans isolates. The presence of 1 in the GXM of Cap70 is consistent with the extra xylose found relative to that in isolate B-3501. The mannose:xylose:glucuronic acid:O-acetyl molar ratio of Cap70 GXM is 3.00:1.73:0.78:1.75, while the same ratio for B-3501 and other serotype D isolates is approximately 3.00:1.00:0.80:1.75. Methylation analysis confirmed that the GXM of Cap70 contains unsubstituted, monosubstituted (2-linked), and disubstituted (2- and 4-linked) mannose in a ratio of 0.87:1.75:0.38. Dot blot immunoassay indicates that Cap70 is a serotype D isolate like its parent strain.

Acetylation↗
PubMed1999

Ploidy of serotype AD strains of Cryptococcus neoformans.

Twenty-four serotype AD strains of Cryptococcus neoformans were tested for ploidy and mating type. These included 13 natural isolates (1 from a patient, 1 from peach juice, 11 from pigeon droppings), 2 single clones from one of these natural isolates, 7 F1 progeny from a self-fertile strain and 2 F1 progeny of a cross between a strain from a patient (serotype A, alfa-mating type: MATalfa) and a tester strain (serotype D, a-mating type: MATa). Six strains (2 of natural isolates, 1 of single clone and 3 of F1 progeny) were MATalfa, 1 of F1 progeny was MATa, 4 (1 of natural isolate, 1 of single clone and 2 of F1 progeny) were a-alfa-mating type (MATa-alfa) and 13 (10 of natural isolates and 3 of F1 progeny) were untypable. Most strains, regardless of mating type, were diploid.

Cryptococcus neoformans↗
PubMed2005

Pde1 phosphodiesterase modulates cyclic AMP levels through a protein kinase A-mediated negative feedback loop in Cryptococcus neoformans.

The virulence of the human pathogenic fungus Cryptococcus neoformans is regulated by a cyclic AMP (cAMP)-dependent protein kinase A (PKA) signaling cascade that promotes mating and the production of melanin and capsule. In this study, genes encoding homologs of the Saccharomyces cerevisiae low- and high-affinity phosphodiesterases, PDE1 and PDE2, respectively, were deleted in serotype A strains of C. neoformans. The resulting mutants exhibited moderately elevated levels of melanin and capsule production relative to the wild type. Epistasis experiments indicate that Pde1 functions downstream of the Galpha subunit Gpa1, which initiates cAMP-dependent signaling in response to an extracellular signal. Previous work has shown that the PKA catalytic subunit Pka1 governs cAMP levels via a negative feedback loop. Here we show that a pde1Delta pka1Delta mutant strain exhibits cAMP levels that are dramatically increased ( approximately 15-fold) relative to those in a pka1Delta single mutant strain and that a site-directed mutation in a consensus PKA phosphorylation site reduces Pde1 function. These data provide evidence that fluctuations in cAMP levels are modulated by both Pka1-dependent regulation of Pde1 and another target that comprise a robust negative feedback loop to tightly constrain intracellular cAMP levels.

Amino Acid Sequence↗
PubMed1998

Assimilation of xylose, mannose, and mannitol for synthesis of glucuronoxylomannan of Cryptococcus neoformans determined by 13C nuclear magnetic resonance spectroscopy.

Cryptococcus neoformans NIH 409 was cultured in a defined medium containing D-[1-13C]xylose (Xyl), D-[1-13C]mannose (Man), or D-[1-13C]mannitol as the sole carbon source. The distribution of 13C in the Man, Xyl, glucuronic acid (GlcA), and O-acetyl constituents of native and de-O-acetylated glucuronoxylomannan (GXM) was determined by one-dimensional 13C nuclear magnetic resonance spectroscopy. The carbon chain of Man was incorporated intact into GXM since 13C was observed only in carbon 1 of Man, GlcA, and Xyl. The carbon chain of mannitol was incorporated intact into GXM since 13C was observed only in carbons 1 and 6. This was expected since mannitol has an axis of symmetry. The carbon chain of Xyl was identified only in carbons 1 and 3 of Man, GlcA, and Xyl. This pattern of labeling is consistent with the assimilation of Xyl through the pentophosphate pathway.

Acetylation↗
PubMed1996

Predictors of outcome in Cryptococcus neoformans var. gattii meningitis.

In Papua New Guinea, Cryptococcus neoformans var. gattii meningitis has a high fatality rate even in immunocompetent patients. Our retrospective study attempted to identify marker of poor prognosis. Of 88 immunocompetent patients, 30 (34.1%) died, usually soon after admission, and mortality was higher in men (p = 0.025) and older patients (p = 0.039). Death was associated with altered consciousness (p < 0.001), a history of convulsions prior to treatment (p = 0.002) and a maximum systolic blood pressure of > 150 mmHg (p = 0.017). These data suggest that death results from raised intracranial pressure and subsequent tentorial herniation. However, CSF opening pressure measured on admission was raised in 29/36 (81%) patients and did not predict outcome. In survivors, relapse was uncommon and was not predicted by discharge serum cryptococcal antigen titres, which were frequently raised on completion of therapy in asymptomatic patients. Mortality may be reduced if efforts are made to lower intracranial pressure in those patients who present with markers of poor prognosis.

Adolescent↗
PubMed1984

Enzyme immunoassay detection of IgM to galactoxylomannan of Cryptococcus neoformans.

Antibodies against the major capsular polysaccharide of Cryptococcus neoformans, glucuronoxylomannan (GXM), and a minor secreted polysaccharide, galactoxylomannan (GalXM), were surveyed by indirect enzyme immunoassay (EIA) in patients with cryptococcosis, with other mycoses, and in normal controls. Measurement of IgG levels against GalXM revealed cross reactions in candidiasis patients that were reduced by adsorption with Candida albicans cell walls. Measurement of IgM levels were subject to fewer cross reactions. The combination of adsorption with C albicans cell walls and measurement of IgM detected antibodies in 12 of 55 cryptococcosis patients. An end point equal to or greater than a titer of 1/16 excluded reactions in normals and limited cross reactivity in candidiasis patients to below 7%. This test has potential diagnostic significance in cryptococcosis patients who show no evidence of cryptococcal antigen circulating in the cerebrospinal fluid or serum. Reactions in this IgM assay were not spuriously due to rheumatoid factor. The major capsular GXM was much less serologically active and was subject to cross reactions with agents of bacterial sepsis. The specificity of the GalXM is directed mainly by the mannose and to a lesser extent by galactosyl residues.

Antibodies, Anti-Idiotypic↗