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PubMed2000

Intracellular parasitism by Histoplasma capsulatum: fungal virulence and calcium dependence.

Histoplasma capsulatum is an effective intracellular parasite of macrophages and causes the most prevalent fungal respiratory disease in the United States. A "dimorphic" fungus, H. capsulatum exists as a saprophytic mold in soil and converts to the parasitic yeast form after inhalation. Only the yeasts secrete a calcium-binding protein (CBP) and can grow in calcium-limiting conditions. To probe the relation between calcium limitation and intracellular parasitism, we designed a strategy to disrupt CBP1 in H. capsulatum using a telomeric linear plasmid and a two-step genetic selection. The resultingcbp1 yeasts no longer grew when deprived of calcium, and they were also unable to destroy macrophages in vitro or proliferate in a mouse model of pulmonary infection.

Alleles↗
PubMed1983

Comparison of ketoconazole and amphotericin B in interference with thymidine uptake by and blastogenesis of lymphocytes stimulated with Histoplasma capsulatum antigens.

Human peripheral blood lymphocytes stimulated with Histoplasma capsulatum yeasts were exposed in culture to graded concentrations of ketoconazole or amphotericin B and subsequently assessed for membrane integrity, thymidine uptake, and blastogenesis. Lymphocyte reactivity varied with concentration and duration of exposure to ketoconazole. Overt membrane toxicity resulted from exposure to 40 micrograms of ketoconazole per ml for 5 days, diminished thymidine uptake occurred with concentrations as low as 5 micrograms/ml, and 15 to 20 micrograms/ml caused a marked decrease in thymidine uptake and eventually diminished blastogenesis. The antilymphocyte action of ketoconazole was neutralized by increasing the concentration of human serum in cultures to 40% regardless of its cholesterol content. Amphotericin B activity was qualitatively similar but less pronounced.

Amphotericin B↗
PubMed1986

Comparison of the in vitro and in vivo activity of the bis-triazole derivative UK 49,858 with that of amphotericin B against Histoplasma capsulatum.

The antifungal activity of UK 49,858, a difluorophenyl bis-triazole derivative, was evaluated in vitro against seven strains of Histoplasma capsulatum and in vivo in AKR and C57BL/6 murine models of histoplasmosis. UK 49,858 had a lower toxicity for AKR and C57BL/6 mice than amphotericin B did. The therapeutic index of UK 49,858 was 4.3 for AKR mice and 7.1 for C57BL/6; with amphotericin B it was 2 for both mouse strains. Given orally, UK 49,858 compared favorably with amphotericin B given intraperitoneally in either AKR or C57BL/6 mice infected with H. capsulatum.

Amphotericin B↗
PubMed1990

In vitro and in vivo activities of Sch 39304, fluconazole, and amphotericin B against Histoplasma capsulatum.

The antifungal activities of amphotericin B and two triazoles, Sch 39304 and fluconazole, were tested against Histoplasma capsulatum. In this study Sch 39304 compared favorably with amphotericin B in treating histoplasmosis in normal and leukopenic mice, whereas fluconazole was much less active. The differences in the efficacies of the triazoles appeared to be due to differences in their pharmacokinetics and the dosage schedule that was used. For amphotericin B there was a good correlation between in vitro and in vivo efficacy, but this was not true of the triazole derivatives. These results further demonstrate that, with the methods used in this study, in vitro susceptibility testing of triazoles may not be predictive of in vivo activity against isolates of H. capsulatum.

Amphotericin B↗
PubMed1995

Inhibition of growth of Histoplasma capsulatum yeast cells in human macrophages by the iron chelator VUF 8514 and comparison of VUF 8514 with deferoxamine.

Histoplasma capsulatum requires intracellular iron to survive and multiply within human and murine macrophages (M phi). Thus, iron chelators may be useful compounds in the treatment of histoplasmosis. In the present study we compared the efficacies of five different iron chelators with deferoxamine (DEF) for their capacity to inhibit the growth of H. capsulatum yeast cells in culture medium and within human M phi. Of the agents tested, only one, VUF 8514, a 2,2'-bipyridyl analog, was found to be effective. VUF 8514 inhibited the growth of yeast cells in tissue culture medium and within M phi in a dose-response fashion. In tissue culture medium, the 50% effective dose (ED50) of VUF 8514 was 30 nM and the ED50 of DEF was 1 mM. In human M phi, the ED50 of VUF 8514 was 520 nM and the ED50 of DEF was 4 mM. Thus, VUF 8514 was effective at a concentration 7.7 x 10(3)-fold lower than DEF in inhibiting the growth of yeast cells in M phi. Inhibition of the intracellular growth of yeast cells by VUF 8514 was reversed by holotransferrin and iron nitriloacetate, an iron compound that is soluble at neutral to alkaline pH. Thus, VUF 8514 inhibits the intracellular growth of yeast cells by acting as an iron chelator rather than through its capacity as a weak base. These data suggest that the hydroxamic acid siderophore of H. capsulatum yeast cells competes successfully for iron against some iron chelators but not others and that VUF 8514 may be a potential therapeutic agent for the treatment of histoplasmosis.

2,2'-Dipyridyl↗
PubMed2000

In vitro activities of voriconazole, itraconazole, and amphotericin B against Blastomyces dermatitidis, Coccidioides immitis, and Histoplasma capsulatum.

The in vitro activity of voriconazole was compared to those of itraconazole and amphotericin B against the mold forms of 304 isolates of three dimorphic fungi, Blastomyces dermatitidis, Coccidioides immitis, and Histoplasma capsulatum. MICs were determined by a broth microdilution adaptation of the National Committee for Clinical Laboratory Standards M27-A procedure. RPMI 1640 medium was used for tests with voriconazole and itraconazole, whereas Antibiotic Medium 3 with 2% glucose was used for amphotericin B. Minimum fungicidal concentrations (MFCs) were also determined. Amphotericin B was active against all three dimorphic fungi, with MICs at which 90% of the isolates tested are inhibited (MIC(90)s) of 0.5 to 1 microg/ml. Itraconazole had MIC(90)s of 0.06 microg/ml for H. capsulatum, 0.125 microg/ml for B. dermatitidis, and 1 microg/ml for C. immitis. The MIC(90)s of voriconazole were 0.25 microg/ml for all three fungi. Amphotericin B was fungicidal for B. dermatitidis and H. capsulatum with MFCs at which 90% of strains tested are killed (MFC(90)s) of 0.5 and 2 microg/ml, respectively. It was less active against C. immitis, with MFCs ranging from 0.5 to >16 microg/ml. Voriconazole and itraconazole were lethal for most isolates of B. dermatitidis, with MFC(50)s and MFC(90)s of 0.125 and 4 microg/ml, respectively. Both azoles were fungicidal for some isolates of H. capsulatum, with MFC(50)s of 2 and 8 microg/ml for itraconazole and voriconazole, respectively; neither had a lethal effect upon C. immitis. Our results suggest that voriconazole possesses promising activity against these important human pathogens.

Amphotericin B↗
PubMed2002

Melanization of Cryptococcus neoformans and Histoplasma capsulatum reduces their susceptibilities to amphotericin B and caspofungin.

The fungal pathogens Cryptococcus neoformans and Histoplasma capsulatum produce melanin-like pigments in the presence of L-dopa in vitro and during mammalian infection. We investigated whether melanization affected the susceptibilities of the fungi to amphotericin B, caspofungin, fluconazole, itraconazole, or flucytosine (5FC). Using the standard macrodilution MIC protocol (the M27A protocol) of the National Committee for Clinical Laboratory Standards for yeast, we found no difference in the susceptibilities of melanized and nonmelanized C. neoformans and H. capsulatum isolates. Killing assays demonstrated that melanization reduced the susceptibilities of both fungi to amphotericin B and caspofungin. Laccase-deficient C. neoformans cells grown with L-dopa were significantly more susceptible than congenic melanin-producing yeast to killing by amphotericin B or caspofungin. Preincubation of amphotericin B or caspofungin with melanins decreased their antifungal activities. Elemental analysis of melanins incubated with amphotericin B or caspofungin revealed an alteration in the C:N ratios of the melanins, which indicated binding of these drugs by the melanins. In contrast, incubation of fluconazole, itraconazole, or 5FC with melanins did not significantly affect the antifungal efficacies of the drugs or the chemical composition of the melanins. The results suggest a potential explanation for the inefficacy of caspofungin against C. neoformans in vivo, despite activity in vitro. Furthermore, the results indicate that fungal melanins protect C. neoformans and H. capsulatum from the activities of amphotericin B and caspofungin and that this protection is not demonstrable by standard broth macrodilution assays.

Amphotericin B↗
PubMed1974

Effects of rifamycin derivatives, alone and in combination with amphotericin B, against Histoplasma capsulatum.

Several derivatives of rifamycin SV inhibited ribonucleic acid synthesis and decreased the viability of Histoplasma capsulatum. Both of these effects were enhanced by low concentrations of amphotericin B. The relative potency of the different rifamycin derivatives against H. capsulatum, when used in combination with amphotericin B or alone, was the same as that reported for the inhibition of the reverse transcriptase of ribonucleic acid tumor viruses.

Amphotericin B↗
PubMed1975

Response of yeast and mycelial phases of Histoplasma capsulatum to amphotericin B and actinomycin D.

The dimorphic fungus Histoplasma capsulatum exists in two phases: a unicellular yeast form at 37 C and a mycelium at 25 C. We have found that these two phases have selective drug susceptibilities. The mycelial form of H. capsulatum was much more susceptible to the polyene antibiotic amphotericin B than the yeast form; in contrast, the yeast form was more susceptible to the antibiotic actinomycin D. The changes in susceptibility occurred early in the transition between the two phases and permitted the transitions to be blocked by sublethal concentrations of the appropriate drugs.

Amphotericin B↗
PubMed1986

Adhesion of the clay minerals montmorillonite, kaolinite, and attapulgite reduces respiration of Histoplasma capsulatum.

The respiration of three phenotypes of Histoplasma capsulatum, the causal agent of histoplasmosis in humans, was markedly reduced by low concentrations of montmorillonite but was reduced less by even higher concentrations of kaolinite or attapulgite (palygorskite). The reduction in respiration followed a pattern that suggested saturation-type kinetics: an initial sharp reduction that occurred with low concentrations of clay (0.01 to 0.5% [wt/vol]), followed by a more gradual reduction with higher concentrations (1 to 8%). Increases in viscosity (which could impair the movement of O2) caused by the clays were not responsible for the reduction in respiration, and the clays did not interfere with the availability of nutrients. Scanning electron microscopy after extensive washing showed that the clay particles were tightly bound to the hyphae, suggesting that the clays reduced the rate of respiration of H. capsulatum by adhering to the mycelial surface and, thereby, interfered with the movement of nutrients, metabolites, and gases across the mycelial wall.

Adhesiveness↗
PubMed1986

Interactions between clay minerals and siderophores affect the respiration of Histoplasma capsulatum.

The reduction in the respiration of Histoplasma capsulatum in broth culture caused by montmorillonite appeared to be the result, in part, of the interference by the clay with the iron nutrition of the fungus. This interference was apparently the result of the adsorption by the clay of the iron-transporting siderophore (deferricoprogen B) produced by the fungus, as the reduction in respiration was partially alleviated by the addition of foreign siderophores. Neither kaolinite nor attapulgite (palygorskite) appeared to adsorb significant amounts of the siderophores, probably because of the low cation exchange capacity and specific surface area of kaolinite and the inaccessibility of adsorption sites in the fibrous attapulgite. These observations, in addition to the adhesion of montmorillonite to the hyphae, suggest mechanisms that may explain the discrete geographic distribution of this fungus, which is pathogenic to humans and which has been isolated essentially only from soils that do not contain montmorillonite.

Adsorption↗
PubMed1968

Reduction of a tetrazolium salt in determining growth activity of yeast-phase Histoplasma capsulatum.

A colorimetric method using a tetrazolium compound, 3,4,5-dimethylthiozalil-(1 or 2),2,5-diphenyltetrazolium bromide (TTBr), was developed for studying the growth activity of yeast-phase Histoplasma capsulatum. Materials extracted in phosphate buffer, pH 7.0, from cells at different stages of growth reduced TTBr. Colorimetric changes were correlated with enzymatic activity. Under standardized conditions specified herein, the optical density of the reduced tetrazole was an index of the growth activity of the organism.

Colorimetry↗
PubMed1970

Growth of Histoplasma capsulatum. VI. Maintenance of the mycelial phase.

A medium is described for the maintenance of the mycelial phases of Histoplasma capsulatum in their "original" condition of sporulation. A yeast phase medium is reemphasized, not only for conversion and support of the yeast phase, but as an indirect method of maintaining the mycelial characteristics as originally observed.

Agar↗
PubMed1972

Factors influencing the production of H and M antigens by Histoplasma capsulatum: development and evaluation of a shake culture.

Studies were undertaken to improve the production of histoplasmin for use in complement-fixation tests and in the determination of H and M antibodies. A shake culture method performed at 25 C was developed with a yeast-phase inoculum. Eight strains of Histoplasma were tested in three synthetic media to evaluate the effects of strain and medium on H and M antigen production. Intrastrain variation was negligible, and antigen production was reproducible. All of the strains produced H antigen; six strains produced both H and M antigens, and two produced only H antigen. The time of H and M antigen appearance varied with the medium; M antigen appearance was dependent upon the strain and medium used. Titers of M antigen appeared to be greater in stagnant culture.

Antibodies↗
PubMed1972

Factors influencing the production of H and M antigens by Histoplasma capsulatum: effect of physical factors and composition of medium.

Stagnant culture methods have permitted only limited physiological studies of the production of H and M antigens by Histoplasma capsulatum because, with such methods, antigen production is uncontrolled. In this investigation, a shake culture method was used to convert yeast-phase inoculum to mycelialphase growth at 25 C. Results strongly suggest that the release of H and M antigens relates to autolysis of the cells. Among the factors influencing production of H and M antigens under shaking conditions, choice of strain was the most important. Alterations of carbon or nitrogen source or variations in amino acid to carbohydrate ratios had limited influence on antigen production. With a strain that produced both H and M antigens, however, proportions of titers of M to H antigens could be made to vary considerably by changes in the medium, the pH, and the temperature. Results suggest that the source of M antigen during autolysis is enzymatic dissolution of the cell wall. The source of H antigen is more obscure. Production of both antigens may be differentially controlled under conditions of good reproducibility by a correct choice of strain and manipulation of culture medium.

Antigens↗
PubMed1972

Isolation of a new soluble antigen from the yeast phase of Histoplasma capsulatum.

A method is described by which a soluble antigen was prepared from the yeast phase of Histoplasma capsulatum. This soluble preparation had a specificity greater than that of whole-cell yeast-phase antigens. In complement fixation tests with sera from human cases of histoplasmosis, blastomycosis, and coccidioidomycosis, the soluble antigen reacted in 12.1% of 141 tests with heterologous sera, whereas conventional whole-cell yeast antigens reacted in 47.3% of 91 tests with heterologous sera. The reactivities of the two types of antigens with homologous sera were essentially the same.

Antigens, Fungal↗
PubMed1994

Immunochemical analysis of the H and M glycoproteins from Histoplasma capsulatum.

The H and M antigens of Histoplasma capsulatum are glycoproteins, and both possess epitopes found on the C antigen, a cross-reactive galactomannan shared by the major genera of systemic dimorphic fungi. We modified the H and M glycoproteins by chemical and enzymatic digestion to determine the relative contributions of the carbohydrate and protein moieties to the immunological reactivities and the apparent molecular weights of these antigens. Endoglycosidases with known action patterns were used to determine the nature of the glycopeptide bonds in the H and M antigens. The effects of these treatments were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, lectin binding, and enzyme-linked immunoelectrotransfer blots probed with polyclonal and monoclonal antibodies (MAbs). Oxidation with 100 mM periodate destroyed the common fungal epitope recognized by MAb CA1-CB4 and nearly all of the concanavalin A-binding sites on both the H and M antigens; it also caused the molecular mass of the M antigen to shift from 94 to 88 kDa. Treatment of samples with O-glycanase had little, if any, effect on the H and M glycoproteins. On the other hand, treatments with endo-beta-N-acetylglucosaminidase H, and particularly peptide N-glycoproteins F (PNGase F), produced pronounced shifts in the M(r) but did not completely eliminate concanavalin A- or MAb CA1-CB4-binding sites. PNGase F treatment caused the molecular mass of the H antigen to shift from 116 to 94 kDa and that of the M antigen to shift from 94 to 74 kDa. The susceptibilities of the H and M glycoproteins to endo-N-acetyl-beta-D-glucosaminidases suggest that their glycosidic moieties are N linked.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibody Specificity↗