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PubMed1975

Improved culture method for the isolation of Histoplasma capsulatum and Blastomyces dermatitidis form contaminated specimens.

Studies were performed to evaluate a method for selective isolation of Histoplasma capsulatum and Blastomyces dermatitidis from contaminated specimens. Ammonium hydroxide placed on an agar medium surface was found to inhibit the growth of many bacteria, yeasts, and saphrophytic fungi normally found in specimens such as animal tissues and sputum. In one study involving the culture of B. dermatitidis from canine tissues, 24% more isolations were obtained on a medium using NH4OH compared with a similar medium. Increases in the isolation of H. capusulatum from sputum specimens were also obtained, ranging from 20 to 32% compared with four other media without NH4OH.

Animals↗
PubMed1981

Use of the exoantigen test to identify blastomyces dermatitidis, coccidioides immitis, and Histoplasma capsulatum in mixed cultures.

Cultures of Blastomyces dermatitidis, Coccidioides immitis, and Histoplasma capsulatum were inoculated with each of five saprophytes to simulate contaminated cultures. The cultures were extracted and tested in the immunodiffusion exoantigen test. Twenty-nine of 30 cultures were correctly identified. The saprophytes did not appear to interfere with the exoantigen test.

Antigens, Fungal↗
PubMed2001

Characterization of cerebrosides from the thermally dimorphic mycopathogen Histoplasma capsulatum: expression of 2-hydroxy fatty N-acyl (E)-Delta(3)-unsaturation correlates with the yeast-mycelium phase transition.

Cerebroside (monohexosylceramide) components were identified in neutral lipids extracted from both the yeast and mycelial forms of the thermally dimorphic mycopathogen Histoplasma capsulatum. The components were purified from both forms and their structures elucidated by 1- and 2-dimensional nuclear magnetic resonance (NMR) spectroscopy, electrospray ionization mass spectrometry (ESI-MS), and low energy tandem collision-induced dissociation mass spectrometry (ESI-MS/CID-MS). Both components were characterized as beta-glucopyranosylceramides (GlcCers) containing (4E,8E)-9-methyl-4,8-sphingadienine as the long-chain base, attached to 18-carbon 2-hydroxy fatty N-acyl components. However, while the fatty acid of the yeast form GlcCer was virtually all N-2'-hydroxyoctadecanoate, the mycelium form GlcCer was characterized by almost exclusive expression of N-2'-hydroxy-(E)-delta(3)-octadecenoate. These results suggest that the yeast-mycelium transition is accompanied by up-regulation of an as yet uncharacterized ceramide or cerebroside 2-hydroxy fatty N-acyl (E)-delta(3)-desaturase activity. They also constitute further evidence for the existence of two distinct pathways for ceramide biosynthesis in fungi, since glycosylinositol phosphorylceramides (GIPCs), the other major class of fungal glycosphingolipids, are found with ceramides consisting of 4-hydroxysphinganine (phytosphingosine) and longer chain 2-hydroxy fatty acids. In addition to identification of the major glucocerebroside components, minor components (< 5%) detectable by molecular weight differences in the ESI-MS profiles were also characterized by tandem ESI-MS/CID-MS analysis. These minor components were identified as variants differing in fatty acyl chain length, or the absence of the sphingoid 9-methyl group or (E)-delta(8)-unsaturation, and are hypothesized to be either biosynthetic intermediates or the result of imperfect chemical transformation by the enzymes responsible for these features. Possible implications of these findings with respect to chemotaxonomy, compartmentalization of fungal glycosphingolipid biosynthetic pathways, and regulation of morphological transitions in H.capsulatum and other dimorphic fungi are discussed.

Carbohydrate Conformation↗
PubMed1980

Interaction of Histoplasma capsulatum with human platelets.

Thrombocytopenia is a common accompaniment of disseminated histoplasmosis. The yeast form of Histoplasma capsulatum does not directly injure human platelets freed of plasma. Preincubation of H. capsulatum with plasma enabled it to induce prompt platelet aggregation and selective release of [3H]serotonin without release of lysosomal beta-glucuronidase and the cytoplasmic marker, lactate dehydrogenase. Platelet aggregation was mediated by adenosine diphosphate, as shown by the blocking of the reaction by apyrase. Indomethacin inhibited both aggregation and serotonin release, indicating their dependence on prostaglandin synthesis by platelets. Plasma IgG conferred [3H]serotonin-releasing activity after complexing with yeasts, and plasma fibrinogen was necessary for platelet aggregation; classical and alternative complement pathways were not involved. The interaction of H. capsulatum with human platelets, mediated by IgG and fibrinogen without complement, represents a new attribute of this fungal pathogen and may contribute to thrombocytopenia complicating disseminated histoplasmosis.

Blood Platelets↗
PubMed1980

Transferrin-dependent growth inhibition of yeast-phase Histoplasma capsulatum by human serum and lymph.

Nonspecific host defense mechanisms that may limit growth of yeast-phase Histoplasma capsulatum in vivo were examined using an in vitro system of cell-free liquid culture. Native human transferrin in serum and lymph, or purified transferrin added to serum-free medium, inhibited yeast replication 10- to 50-fold. Supplementation of serum with iron to complete or almost complete saturation of total iron-binding capacity neutralized inhibition. Substitution of Zn++, Mn++, or Cu++ for Fe++ did not affect inhibition. Neither complement nor antibody was a relevant factor. Results of culture in medium with unsaturated transferrin followed by replenishment with iron indicated that iron deprivation was either fungistatic or fungicidal, depending on the yeast strain and, in serum-free medium, on the iron content of transferrin. Transferrin-dependent fungistasis was associated with morphologic alteration of yeasts as determined by electron microscopy. Thus, susceptibility of yeast-phase H. capsulatum to iron starvation by unsaturated transferrin may contribute to their low virulence in vivo.

Antifungal Agents↗
PubMed1989

Comparison of sandwich solid-phase radioimmunoassay and two enzyme-linked immunosorbent assays for detection of Histoplasma capsulatum polysaccharide antigen.

Detection of a Histoplasma capsulatum polysaccharide antigen (HPA) has proved a useful approach to diagnosis of histoplasmosis. Two sandwich enzyme-linked immunosorbent assays (ELISAs) using alkaline phosphatase (AP)-or horseradish peroxidase (HRP)-conjugated antibodies were compared with solid-phase radioimmunoassay (RIA) for detection of HPA. The AP-ELISA and HRP-ELISA were each positive in 17 (89.5%) of 19 urine specimens from patients with disseminated histoplasmosis, while the RIA was positive in 18 (94.7%) of 19. Specimens from patients with nondisseminated histoplasmosis were positive by AP-ELISA in 8 of 32, by HRP-ELISA in 4 of 25, and by RIA in 12 of 25. Of control specimens from patients with other fungal infections, the AP-ELISA was negative in 22 (91.7%) of 24, the HRP-ELISA in 23 (95.8%) of 24, and the RIA in 23 (95.8%) of 24. Reproducibilities AP-ELISA and HRP-ELISA were 95.1% and 95.1%, respectively. Thus, AP-ELISA and HRP-ELISA appear less sensitive than RIA and may be falsely negative in specimens containing low levels of HPA.

Antigens, Fungal↗
PubMed1990

The intracellular fate of Histoplasma capsulatum in human macrophages is unaffected by recombinant human interferon-gamma.

Human alveolar, peritoneal, and cultured macrophages were exposed in vitro to human recombinant interferon-gamma (rHuIFN-gamma) and were tested for their ability to inhibit intracellular replication of yeast-phase Histoplasma capsulatum. Exposure at various concentrations, and for different time periods, failed to activate the macrophages to inhibit multiplication of intracellular yeast. Macrophages were, however, activated by rHuIFN-gamma as shown by their ability to inhibit intracellular replication of Trypanosoma cruzi and by their enhanced production of superoxide when stimulated by phorbol myristate acetate. These data indicate that rHuIFN-gamma by itself does not activate human macrophages to inhibit intracellular proliferation of yeast-phase H. capsulatum.

Cells, Cultured↗
PubMed1990

Temperature-sensitive variants of Histoplasma capsulatum isolated from patients with acquired immunodeficiency syndrome.

Histoplasma capsulatum isolates from three St. Louis area AIDS patients with disseminated histoplasmosis were found to be closely related to the temperature-sensitive, previously unique, Downs strain based on growth phenotype and restriction fragment length polymorphisms (RFLP) involving mitochondrial DNA, ribosomal DNA, and the yps-3 gene. H. capsulatum isolates from five non-AIDS patients in the St. Louis area with disseminated histoplasmosis or chronic pulmonary histoplasmosis had the growth phenotype and RFLP pattern characteristic of most strains isolated from other regions of the USA.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Tumor necrosis factor-alpha plays a role in host defense against Histoplasma capsulatum.

Tumor necrosis factor-alpha was detected in supernatants collected from BALB/c mouse peritoneal macrophages incubated continuously with Histoplasma capsulatum. The levels of TNF alpha measured by actinomycin D bioassay peaked within hours after exposure and then greatly declined by 24 h. TNF alpha was also measured in bronchoalveolar lavage fluid from BALB/c mice challenged intranasally with H. capsulatum. Lavage fluid TNF alpha levels exhibited the same pattern as the in vitro supernatants; they peaked within hours after challenge and lower levels were detected at 24 h. Treatment of mice with anti-TNF alpha antibody accelerated mortality in response to systemic infection and significantly increased tissue colony counts in the liver and spleen. In the murine model, TNF alpha is produced in response to H. capsulatum and appears to play some role in host defense to infection.

Animals↗
PubMed1991

Fungistatic activity of human neutrophils against Histoplasma capsulatum: correlation with phagocytosis.

The interaction of human polymorphonuclear leukocytes (PMNL) and Histoplasma capsulatum was studied. In limiting dilution assays and in a 2-h coculture system, PMNL were ineffective in killing H. capsulatum whereas Candida albicans was readily killed. Although PMNL could not reduce inoculum colony-forming units of H. capsulatum in short-term assays, they were highly fungistatic in 24- (47%-55%) and 72-h (65%-75%) cocultures. Phagocytosis of yeast cells by PMNL was 81.3% +/- 3.7%. Fungistasis persisted even though PMNL viability decreased with time. Fungistatic activity of PMNL was dose dependent. Fungistasis was verified by direct hemocytometer counts of fungal units. In transwell experiments, PMNL contact with H. capsulatum was required for fungistatic activity. Lymphocytes, PMNL lysates, or PMNL supernatants were not fungistatic in this system.

Candida albicans↗
PubMed1995

Macrophages from human immunodeficiency virus-positive persons are defective in host defense against Histoplasma capsulatum.

The phagocytic and fungistatic activity of monocyte-derived macrophages from human immunodeficiency virus (HIV)-positive persons against Histoplasma capsulatum yeasts was determined. Macrophages from HIV-positive patients were profoundly deficient in their capacity to recognize and bind H. capsulatum, but ingestion of bound yeasts was normal. The binding of H. capsulatum by patient macrophages tended to decrease with a decrease in CD4+ T lymphocyte counts. Another major defect was that patient macrophages were more permissive for the intracellular growth of H. capsulatum. Macrophages from 22 of 58 patients showed a > or = 2-fold increase in intracellular growth compared with control macrophages. Thus, in addition to defects in cell-mediated immunity caused by a loss of CD4+ T cells, macrophages from HIV-positive patients exhibit intrinsic defects in macrophage function against H. capsulatum that may contribute to the increased susceptibility of HIV-positive patients to disseminated histoplasmosis.

AIDS-Related Opportunistic Infections↗
PubMed1996

A protective domain of heat-shock protein 60 from Histoplasma capsulatum.

Vaccination with recombinant (r) hsp60 protects mice against Histoplasma capsulatum. To map the domain of rhsp60 that confers protection, four gene segments were cloned into pET19b and expressed in Escherichia coli. rhsp60 fragments were tested for their capacity to induce proliferation by sensitized splenocytes and to protect BALB/c and C57BL/6 mice. All polypeptides stimulated cells from BALB/c mice immunized with yeasts or with rhsp60. Fragment 3 caused the most vigorous response by cells from mice immunized yeasts, and fragment 1 caused the most vigorous response by cells from mice immunized with rhsp60. Splenocytes from yeast-immunized C57BL/6 mice did not recognize any polypeptide. In contrast, cells from C57BL/6 mice inoculated with rhsp60 responded to all fragments but most intensely to fragment 2. In both strains, fragment 3 conferred protection against sublethal and lethal challenges. Thus, a common protective domain of hsp60 has been identified.

Animals↗
PubMed2006

Activity of newer triazoles against Histoplasma capsulatum from patients with AIDS who failed fluconazole.

OBJECTIVES: To determine the activity of newer triazoles against strains of Histoplasma capsulatum resistant to fluconazole. METHODS: Susceptibility testing was performed on 17 paired pre- and post-treatment H. capsulatum isolates from patients with AIDS who failed fluconazole. RESULTS: The median MICs of fluconazole, voriconazole, and posaconazole and ravuconazole for the pre-treatment isolates were 1 mg/L, 0.015 mg/L and <0.007 mg/L, respectively. A 4-fold or greater increase in the MIC of fluconazole and voriconazole was observed in 12 and 7 of the post-treatment isolates, respectively; the median fold increases in MIC were 8 and 2.1, respectively. No MIC increases were observed for posaconazole and ravuconazole. One pair of isolates exhibiting reduced susceptibility was examined in more detail. A single amino acid substitution (at tyrosine 136) was identified in the active site of the CYP51 protein from the post-treatment isolate, which is presumed to be responsible for reduced susceptibility to voriconazole and fluconazole, analogous to recent observations in Candida albicans. CONCLUSIONS: These findings support careful monitoring for relapse in patients receiving voriconazole treatment for histoplasmosis, particularly in those who were previously treated with fluconazole.

AIDS-Related Opportunistic Infections↗
PubMed1994

The Histoplasma capsulatum antigen assay in disseminated histoplasmosis in children.

Progressive disseminated histoplasmosis is often fatal without treatment and requires rapid and accurate laboratory diagnosis. Radioimmunoassay for Histoplasma capsulatum var. capsulatum antigen has been established as a sensitive and accurate diagnostic technique for disseminated histoplasmosis in adults; this study examines the radioimmunoassay in children. The clinical and laboratory records of 26 patients 18 years old or younger in whom H. capsulatum antigen was detected in urine by radioimmunoassay and at least one other positive corroborative standard test were evaluated. Twenty-two (85%) had disseminated disease, and 4 (15%) had self-limited pulmonary disease. Positive corroborative tests included serologic tests in 17 of 22 (77%) patients tested, tissue stains in 5 of 9 (56%) and fungal cultures in 16 of 24 (67%). Patients with disseminated histoplasmosis had a greater degree of antigenuria than those with self-limited infection. In 20 patients with progressive disease treated with amphotericin B, antigen levels declined, and the decrease in antigenuria correlated with clinical improvement. The radioimmunoassay for H. capsulatum antigen in urine is an important test in the diagnosis of disseminated histoplasmosis and is useful for assessing the efficacy of treatment. The presence of urinary antigen is strong evidence for progressive disease that requires treatment.

Adolescent↗
PubMed1984

Significance of serum antibodies to Histoplasma capsulatum in endemic areas.

To evaluate the specificity of serologic tests for histoplasmosis in an endemic area, we studied sera from 104 consecutive healthy blood donors, testing for antibodies to either histoplasmin or Histoplasma yeast antigen, using complement fixation (CF), radioimmunoassay (RIA), and radial immunodiffusion (ID). Twenty-five subjects (24%) had CF antibody titers of 1:8 or 1:16 to one or both antigens; none had titers above 1:16. Nine subjects (9%) had RIA antibody titers of 1:8 or higher. No titers above 1:8 were found using the yeast antigen; five subjects had titers of greater than 1:16 to histoplasmin using RIA. No precipitin bands were found in any of these subjects. The results of four previous studies in endemic populations yielded similar or lower incidences of positive tests. CF antibody titers to either antigen, RIA antibody titers to yeast antigen of 1:32 or greater, or precipitin bands are rare in persons who live where histoplasmosis is endemic.

Adolescent↗
PubMed1987

Heat-shock proteins induced during the mycelial-to-yeast transitions of strains of Histoplasma capsulatum.

Heat-shock proteins (hsp) were elicited when mycelia of the Downs strain and the more virulent G184A and G222B strains of Histoplasma capsulatum were shifted up to temperatures which induced the mycelial-to-yeast transition (34-40 degrees C). The classes of the major hsp which increased in synthesis in each strain were similar. However, the pattern of synthesis of these proteins at the different temperatures in Downs differed from those in the G184A and G222B strains: hsp synthesis in Downs peaked at 34 degrees C, whereas in G184A and G222B it was highest at 37 degrees C.

Heat-Shock Proteins↗
PubMed1989

Characterization of alpha and beta tubulin genes in the dimorphic fungus Histoplasma capsulatum.

Evidence from our laboratory indicates that microtubules are involved in the differentiation of the dimorphic, pathogenic fungus Histoplasma capsulatum; therefore, we cloned the tubulin genes from a virulent strain of the organism. We report that the H. capsulatum genome contains a single alpha (TUB1) and a single beta (TUB2) tubulin gene rather than the more typical multigene family which is common in even the simplest eukaryotes. Sequence data from these genes reveal a high degree of nucleotide and protein sequence conservation relative to tubulins from other species. The coding regions of TUB1 and TUB2 contain five and eight intervening sequences, respectively. Field inversion gel electrophoresis of H. capsulatum chromosome-sized DNA fragments indicates that the TUB1 and TUB2 genes are unlinked. Potential regulatory elements common to both genes have been identified in the 5' promoter regions. These elements may direct the coordinate expression of TUB1 and TUB2 during differentiation. The cloning and characterization of alpha and beta tubulin genes from H. capsulatum provides the first description of gene structure in this widely distributed pathogenic fungus. Isolation of the tubulin genes will facilitate future studies of tubulin gene expression during the dimorphic phase transitions and clarify the role of microtubules in the differentiation process.

Amino Acid Sequence↗
PubMed1990

A murine monoclonal antibody exhibiting high species specificity for Histoplasma capsulatum var. capsulatum.

A monoclonal antibody (mAb) exhibiting a high degree of species specificity for the yeast phase of the dimorphic fungus Histoplasma capsulatum was produced by a modification of the standard mAb production protocol. The technique for generating mAbs involved the use of the immunosuppressive drug cyclophosphamide to diminish the response in mice to immunodominant cross-reactive epitopes. This mAb exhibited clear specificity and did not react by ELISA with the closely related genera Blastomyces, Paracoccidioides and Sporothrix. In Western blots it recognized a linear determinant on a 70-75 kDa molecule in H. capsulatum antigen, with an extremely faint reactivity to antigens of identical molecular mass derived from Sporothrix and Paracoccidioides, and no reactivity against Blastomyces antigen.

Animals↗