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PubMed1993

Human neutrophil-mediated fungistasis against Histoplasma capsulatum. Localization of fungistatic activity to the azurophil granules.

Human neutrophils (PMN) demonstrated potent fungistatic activity against Histoplasma capsulatum (Hc) yeasts in a sensitive microassay that quantifies the growth of yeasts by the incorporation of [3H]leucine. At a PMN:yeast ratio of 1:2, PMN inhibited the growth of yeasts by 37%. Maximum inhibition of 85% to 95% was achieved at a PMN/yeast ratio of 10:1 to 50:1. Opsonization of the yeasts in fresh or heat-inactivated serum was required for PMN-mediated fungistasis, but ingestion of the yeasts was not required. Recognition and phagocytosis of opsonized yeasts was via PMN complement receptor (CR) type 1 (CR1), CR3, and FcRIII (CD16). PMN fungistatic activity was evident by 2 h, was maximum at 24 h, and persisted up to 5 d. In contrast, yeasts multiplied within monocytes to a greater extent than in culture medium alone. PMN from three patients with chronic granulomatous disease (CGD) inhibited the growth of Hc yeasts by an average of 97%, compared with 86% in three normal controls. Furthermore, preincubation of PMN with the lysosomotropic agent NH4Cl inhibited fungistatic activity in a concentration-dependent manner. Finally, experiments with subcellular fractions of PMN demonstrated that the principal component of the fungistatic activity of PMN was localized in the azurophil granules. These data demonstrate that human PMN possess potent fungistatic activity against Hc yeasts and further show that fungistasis is mediated by antimicrobial agents contained in the azurophil granules.

Cell Adhesion↗
PubMed1994

Chloroquine induces human macrophage killing of Histoplasma capsulatum by limiting the availability of intracellular iron and is therapeutic in a murine model of histoplasmosis.

We investigated the role of intracellular iron on the capacity of Histoplasma capsulatum (Hc) yeasts to multiply within human macrophages (Mphi). Coculture of Hc-infected Mphi with the iron chelator deferoxamine suppressed the growth of yeasts in a concentration-dependent manner. The effect of deferoxamine was reversed by iron-saturated transferrin (holotransferrin) but not by iron-free transferrin (apotransferrin). Chloroquine, which prevents release of iron from transferrin by raising endocytic and lysosomal pH, induced human Mphi to kill Hc. The effect of chloroquine was reversed by iron nitriloacetate, an iron compound that is soluble at neutral to alkaline pH, but not by holotransferrin, which releases iron only in an acidic environment. Chloroquine (40-120 mg/kg) given intraperitoneally for 6 d to Hc-infected C57BL/6 mice significantly reduced the growth of Hc in a dose-dependent manner. At 120 mg/kg there was a 17- and 15-fold reduction (P < 0.01) in CFU in spleens and livers, respectively. The therapeutic effect of chloroquine also correlated with the length of treatment. As little as 2 d of chloroquine therapy (120 mg/kg), when started at day 5 after infection, reduced CFU in the spleen by 50%. Treatment with chloroquine for 10 d after a lethal inoculum of Hc protected six of nine mice; all control mice were dead by day 11 (P = 0.009). This study demonstrates that: (a) iron is of critical importance to the survival and multiplication of Hc yeasts in human Mphi; (b) in vitro, chloroquine induces Mphi killing of Hc yeasts by restricting the availability of intracellular iron; and (c) in vivo, chloroquine significantly reduces the number of organisms in the spleens and livers of Hc-infected mice and can protect mice from a lethal inoculum of Hc yeasts. Thus, chloroquine may be effective in the treatment of active histoplasmosis and also may be useful in preventing relapse of histoplasmosis in patients with acquired immunodeficiency syndromes.

Animals↗
PubMed1995

Murine laminin binds to Histoplasma capsulatum. A possible mechanism of dissemination.

Histoplasmosis, an increasingly important opportunistic infection in immunosuppressed subjects, is characterized by hematogenous dissemination of the yeast from the lung. The mechanism of this dissemination is not fully understood. Laminin, the major glycoprotein of the extracellular matrix, is known to mediate the attachment of various invasive pathogens to host tissues. In the current study, laminin is demonstrated to bind to Histoplasma capsulatum in a rapid, specific, and saturable manner. Scatchard analysis with 125I-labeled laminin revealed an estimated 3.0 x 10(4) binding sites per yeast with an apparent Kd for laminin binding of 1.6 x 10(-9) M. Laminin binding to H. capsulatum was decreased from 62 +/- 1 to 17 +/- 1 ng (P < 0.001) in the presence of 3,000 nM of Ile-Lys-Val-Ala-Val, a pentapeptide within one major cell attachment site of laminin. A 50-kD H. capsulatum laminin-binding protein was demonstrated using an 125I-Ln blot of H. capsulatum cell wall proteins. The 50-kD protein is also recognized by antibodies directed at the 67-kD laminin receptor, suggesting they are related. This study proposes a possible mechanism for H. capsulatum attachment to laminin, an important first step required for the yeast to recognize and traverse the basement membrane.

Amino Acid Sequence↗
PubMed1997

Modulation of the effector function of human macrophages for Histoplasma capsulatum by HIV-1. Role of the envelope glycoprotein gp120.

We have demonstrated that monocyte-derived macrophages (Mphi) from HIV+ individuals are deficient in their capacity to phagocytose Histoplasma capsulatum (Hc) yeasts, and are more permissive for the intracellular growth of Hc. To determine whether these defects in Mphi function were caused by HIV infection of the Mphi and/or by pathological events associated with HIV infection, cultured normal human Mphi were infected with the HIV-1BaL strain. Virus production, quantified by reverse transcriptase activity and p24 antigen, was evident on day 8 after infection and peaked on day 16. On days 12, 16, and 20 after infection, HIV-1-infected Mphi were deficient in their capacity to recognize and bind Hc yeasts compared with control Mphi, and also were more permissive for the intracellular growth of Hc. Culture of normal Mphi with the envelope glycoprotein gp120 inhibited phagocytosis of Hc yeasts by Mphi in a concentration-dependent manner, but did not cause more rapid intracellular growth of Hc. Normal Mphi cultured in the serum of HIV+ individuals with impaired Mphi function subsequently were deficient in their capacity to phagocytose Hc yeasts, and were more permissive for the intracellular growth of yeasts compared with Mphi cultured in normal serum. Conversely, culture of normal Mphi in the serum of HIV+ patients with normal Mphi function did not affect the interaction of Hc yeasts with Mphi. Moreover, when Mphi from HIV+ individuals that were initially defective in host defense against Hc were cultured in normal HIV- serum, normal Mphi function was demonstrated. Adsorption of gp120 from the serum of two HIV+ patients removed the capacity of the serum to cause a Mphi defect in phagocytosis of Hc, but had no effect on the capacity of the serum to cause accelerated intracellular growth. These data demonstrate that observed defects in Mphi interaction with Hc yeasts may be caused by gp120 and other, as yet unknown serum component(s) probably released into serum by HIV-infected cells.

Blood Proteins↗
PubMed2003

Antibodies to a cell surface histone-like protein protect against Histoplasma capsulatum.

A protective role for antibodies has not previously been described for host defense against the pathogenic fungus Histoplasma capsulatum (Hc). Mouse mAb's were generated from mice immunized with Hc yeast that binds the cell surface of Hc. Administration of mAb's before Hc infection reduced fungal burden, decreased pulmonary inflammation, and prolonged survival in a murine infection model. Protection mediated by mAb's was associated with enhanced levels of IL-4, IL-6, and IFN-gamma in the lungs of infected mice. The mAb's increased phagocytosis of yeast by J774.16 cells through a CR3-dependent process. Ingestion of mAb-opsonized Hc by J774.16 macrophage-like cells was associated with yeast cell growth inhibition and killing. The mAb's bound to a 17-kDa antigen expressed on the surface of Hc. The antigen was identified as a histone H2B-like protein. This study establishes that mAb's to a cell surface protein of Hc alter the intracellular fate of the fungus and mediate protection in a murine model of lethal histoplasmosis, and it suggests a new candidate antigen for vaccine development.

Amino Acid Sequence↗
PubMed2005

Apoptosis modulates protective immunity to the pathogenic fungus Histoplasma capsulatum.

Pathogen-induced apoptosis of lymphocytes is associated with increased susceptibility to infection. In this study, we determined whether apoptosis influenced host resistance to the fungus Histoplasma capsulatum. The level of apoptotic leukocytes progressively increased in the lungs of naive and immune mice during the course of H. capsulatum infection. T cells constituted the dominant apoptotic population. Apoptosis was diminished in H. capsulatum-infected gld/gld and TNF-alpha-deficient mice; concomitantly, the fungal burden exceeded that of controls. Treatment of naive and H. capsulatum-immune mice with caspase inhibitors decreased apoptosis but markedly enhanced the severity of infection. Administration of a proapoptotic dose of suramin diminished the fungal burden. The increased burden in recipients of a caspase inhibitor was associated with elevations in IL-4 and IL-10 levels. In the absence of either of these cytokines, caspase inhibition suppressed apoptosis but did not increase the fungal burden. Thus, apoptosis is a critical element of protective immunity to H. capsulatum. Production of IL-4 and IL-10 is markedly elevated when apoptosis is inhibited, and the release of these cytokines exacerbates the severity of infection.

Animals↗
PubMed2002

Comparison of staining methods and a nested PCR assay to detect Histoplasma capsulatum in tissue sections.

To optimize diagnosis of histoplasmosis in tissue sections, 30 spleen specimens from mice, experimentally infected with Histoplasma capsulatum, were examined by H&E, Grocott stain, anti-bacille Calmette-Guerin antibody immunostain, Fungiqual A fluorochrome stain (Drs Reinehr and Rembold, Kandern, Germany), and a nested polymerase chain reaction (PCR) assay. Results were compared with the tissue burden determined by quantitative culture. By applying logistic regression, the nested PCR assay was the most sensitive method, but not significantly more sensitive than the Grocott stain. The 50% quantile to achieve a positive result was determined to be 3 colony-forming units per milligram of spleen tissue for the PCR assay, 11 for the Grocott stain, 27 for the fluorochrome stain, 190 for immunostaining, and 533 for the H&E stain. The Grocott and fluorochrome stains did not differ significantly in detecting fungal elements. The PCR assay unambiguously identified H. capsulatum in tissue sections.

Animals↗
PubMed1997

Bronchopleural fistula and lymphocytic empyema due to Histoplasma capsulatum.

A patient presented with chest pain, fever, and chills and developed a large pleural effusion while receiving antibiotic therapy. On a CT scan of the chest, multiple loculi of fluid were noted, and at surgery, a complex empyema with an associated bronchopleural fistula related to a granulomatous process in the lower lobe of the right lung was demonstrated. Cultures revealed Histoplasma capsulatum in the pleural fluid as well as in the pulmonary parenchymal process.

Bronchial Fistula↗
PubMed1981

Hitchcock's birds, or the increased rate of exposure to histoplasma from blackbird roost sites.

A statewide survey of populations in proximity to blackbird roost sites to determine exposure to histoplasmosis from such sites has demonstrated that a site harboring Histoplasma capsulatum, even though undisturbed, adds significantly to the exposure rate of proximal populations. Disturbance of such a site increases the exposure rate dramatically with or without concurrent clinical cases of histoplasmosis.

Adult↗
PubMed2005

Interaction of Histoplasma capsulatum with human macrophages, dendritic cells, and neutrophils.

Histoplasma capsulatum (Hc) is a dimorphic fungal pathogen indigenous to the Ohio and Mississippi River Valleys in the United States. Infection is initiated by inhalation of microconidia or small mycelial fragments into the terminal bronchioles of the lung. The conidia are taken up by alveolar macrophages (Mphi), in which they convert to the pathogenic yeast phase. The yeasts replicate in the alveolar Mphi and other Mphi recruited to the lung as part of the inflammatory response. Thus, the yeasts are able to disseminate from the lung to other organs, such as the liver and spleen. As a facultative intracellular parasite, the interaction of Hc yeasts with Mphi is a critical component of the host response to infection. In addition, Hc yeasts have critical interactions with inflammatory neutrophils, and with dendritic cells (DCs) in the lung and other organs. Indeed, recent new evidence suggests that DCs may be the key antigen-presenting cells that initiate cell-mediated immunity. Thus, the methods described in this chapter cover quantitation of the binding, ingestion, and intracellular replication of Hc yeasts in human Mphi, DCs, and neutrophils.

Antigen Presentation↗
PubMedDate not supplied

New records of Histoplasma capsulatum from wild animals in the Brazilian Amazon.

Twenty-eight isolates of Histoplasma capsulatum were obtained from eight species of forest mammals from the States of Amazonas, Pará and Rondônia in the Amazon Region of Brazil. Primary isolates were obtained by inoculating triturated liver and spleen tissue intradermally and intraperitoneally in hamsters. Mycological diagnosis in hamsters presenting lesions was confirmed by histopathology and culture on Sabouraud dextrose-agar. Infected hamsters developed signs of disease within two to nine months; all had disseminated visceral lesions and most also had skin lesions at the sites of inoculation. None of the hamsters inoculated with skin macerates of the original hosts developed histoplasmosis, and histopathological examination of the viscera of the wild hosts failed to reveal H. capsulatum. Prevalence of infection was considerably higher in females than in males both for the opossum Didelphis marsupialis and for total wild animals (479) examined. It is proposed that canopy-dwelling mammals may acquire the infection from conidia borne on convective currents in hollow trees with openings at ground-level.

Animals↗
PubMedDate not supplied

[Production and standardization of Paracoccidioides brasiliensis, Histoplasma capsulatum and Aspergillus fumigatus antigens to be used in immunodiagnosis. Comparison between immunodiffusion and immunoelectrophoresis].

Soluble antigens (Ag) from Paracoccidioides brasiliensis, Histoplasma capsulatum and Aspergillus fumigatus were prepared and standardized by double immunodiffusion (DID) and immunoelectroosmophoresis (IEOP). No difference in sensitivity was observed between the two techniques; 100% of standard patient sera were positive with P. brasiliensis and A. fumigatus Ag and 83.3% were positive with H. capsulatum Ag. The specificity of the tests was verified testing 96 sera from patients with paracoccidioidomycosis, histoplasmosis, systemic candidiasis, sporotrichosis, tuberculosis, lung cancer, visceral or cutaneous leishmaniasis and 18 sera from healthy individuals. All the three antigens were 100% specific with the DID (using the identification pattern indicated by the confluence of test serum with standard serum precipitin lines as a positive criterium). However in the IEOP, the specificity varied with each Ag. Positive reactions with P. brasiliensis Ag were observed in 16.7% of histoplasmosis sera and in 10% of cutaneous leishmaniasis sera. On the other hand 31.8% of paracoccidioidomycosis and 10% of cutaneous leishmaniasis sera reacted with H. capsulatum Ag. The high sensitivity and specificity of the DID test, its easy reproducibility and low cost, led us to consider it highly appropriate as a routine procedure for the screening of patients with respiratory infections.

Antigens, Fungal↗
PubMed2004

Interleukin-5 mediates peritoneal eosinophilia induced by the F1 cell wall fraction of Histoplasma capsulatum.

An alkali-insoluble fraction 1 (F1), which contains mainly ss-glucan isolated from the cell wall of Histoplasma capsulatum, induces eosinophil recruitment into the peritoneal cavity of mice. The present study was carried out to determine the participation of interleukin-5 (IL-5) in this process. Inbred C57BL/6 male mice weighing 15-20 g were treated ip with 100 microg of anti-IL-5 monoclonal antibody (TRFK-5, N=7) or an isotype-matched antibody (N=7), followed by 300 microg F1 in 1 ml PBS ip 24 h later. Controls (N=5) received only 1 ml PBS. Two days later, cells from the peritoneal cavity were harvested by injection of 3 ml PBS and total cell counts were determined using diluting fluid in a Neubauer chamber. Differential counts were performed using Rosenfeld-stained cytospin preparations. The F1 injection induced significant (P<0.01) leukocyte recruitment into the peritoneal cavity (8.4 x 10(6) cells/ml) when compared with PBS alone (5.5 x 10(6) cells/ml). Moreover, F1 selectively (P<0.01) induced eosinophil recruitment (1 x 10(6) cells/ml) when compared to the control group (0.07 x 10(6) cells/ml). Treatment with TRFK-5 significantly (P<0.01) inhibited eosinophil recruitment (0.18 x 10(6) cells/ml) by F1 without affecting recruitment of mononuclear cells or neutrophils. We conclude that the F1 fraction of the cell wall of H. capsulatum induces peritoneal eosinophilia by an IL-5-dependent mechanism. Depletion of this cytokine does not have effect on the recruitment of other cell types induced by F1.

Animals↗
PubMed1988

A serendipitous isolate of Histoplasma capsulatum.

This is a report of an unexpected laboratory diagnosis of Histoplasma capsulatum. The fungus was isolated from an acute cellulitic lesion on the forearm of an elderly male patient with a functioning renal transplant. The patient resides within the environs of Brisbane and has not travelled outside Australia. We consider the isolation of H. capsulatum from a rare site in a patient resident in a non-endemic area indicative of a latent opportunistic infection in an immunocompromised patient.

Histoplasma↗
PubMed1986

Immunofluorescent detection of Histoplasma capsulatum in primate experimental ocular histoplasmosis.

We have developed a polyclonal anti-Histoplasma capsulatum antibody to detect H. capsulatum antigens in ocular tissue. Antibodies were specific for H. capsulatum as determined by enzyme linked immunosorbent assay and immunoprecipitation. A total of 21 choroidal histoplasmic lesions in 4 primate eyes (Macaca speciosa and Macaca mulatta), taken at various times from 14 to 60 days after the internal carotid artery injection of yeast phase organisms, were evaluated. Using an indirect immunofluorescent technique, these antibodies stained yeast phase organisms within acute choroidal lesions at 14 days after infection. By 60 days intact organisms were no longer detected; occasional cells, however, contained intracellular inclusions that stained with these antibodies. Although yeast phase organisms are rapidly cleared from the primate choroid, these data indicate that residual H. capsulatum antigens may remain in choroidal lesions after the acute infectious stage. These findings are consistent with the hypothesis that H. capsulatum antigens play a role in the immunologic reactivation of atrophic choroidal scars in ocular histoplasmosis.

Animals↗
PubMed2002

Phylogenetic characterization of Histoplasma capsulatum strains based on ITS region sequences, including two new strains from Thai and Chinese patients in Japan.

Two strains of Histoplasma capsulatum var. capsulatum were isolated in Japan: one from a Thai AIDS patient and the other from a Chinese non-immunocompromised patient. The phylogenetical relationship among the two isolates and reference strains of H. capsulatum from other geographical populations was investigated. Random amplified polymorphic DNA (RAPD) analysis of the two H. capsulatum strains showed that they had RAPD band patterns similar to those of the reference Thai isolates and North American strains, although the patterns differed slightly from those of the reference strains. Phylogeny of thirty geographically diverse H. capsulatum isolates representing the three varieties, var. capsulatum, var. duboisii and var. farciminosum were evaluated using nucleotide sequences of the internal transcribed spacer (ITS) region (ITS1-5.8S rDNA -ITS2). We found that the ITS region contained sufficient information to resolve the phylogenetic relationship among the fungal isolates. An unrooted dendrogram constructed from the ITS sequences showed that thirty strains of H. capsulatum could be classified into eight geographic clades; Asia type (i), South America types A (ii) and B (iii), North American types 1 (iv) and 2 (v), H. duboisii types A (vi) and B (vii), and East Asia type (viii). Based on the ITS region sequence analysis, the two strains isolated from the Thai and Chinese patients in Japan were found to be distinct from Asia type (i) in which eight Thai, one Chinese, one English and one Indonesian isolate were included. Some extent of DNA polymorphism was observed between the North America type 1 isolates and the Thai and Chinese strains isolated in Japan. We believe that the Thai and Chinese isolates were unique and propose a new clade, East Asia type (viii) for the two strains. DNA sequence analysis of the ITS region provided useful information to understand the epidemiology and evolution of H. capsulatum.

Base Sequence↗
PubMed2003

Histoplasma capsulatum variety duboisii isolated in Japan from an HIV-infected Ugandan patient.

A strain of Histoplasma capsulatum var. duboisii (deposited as IFM 50954 in Chiba University) was isolated from the cerebrospinal fluid of a female Ugandan patient infected with HIV. The isolate had in vitro urease activity on Christensen's urea agar slants, although the common belief is that H. capsulatum var. duboisii is urease negative, and is, considered one of the characteristic markers that distinguishes the three varieties of H. capsulatum. Forty H. capsulatum var. capsulatum, five H. capsulatum var. duboisii, and five H. capsulatum var. farciminosum isolates were evaluated for urease activity on Christensen's urea agar slants and for other qualitative and quantitative urease assays of activity. All 50 isolates of H. capsulatum used in this study were positive for urease activity, suggesting that urease activity may be universal characteristic of H. capsulatum. We also compared the urease activity and pathogenicity of seven H. capsulatum isolates that convert into yeast-form cells. Although isolate IFM 50954 showed moderate virulence in mice and moderate urease activity among tested H. capsulatum isolates, there was no correlation between level of urease activity and pathogenicity. In addition, scanning electron microscopy revealed that some microconidia of isolate IFM 50954 formed "double-cell" configurations that were attached to each other by narrow bases.

Animals↗
PubMed2005

Phylogenetic analysis of Histoplasma capsulatum based on partial sequence of the D1/D2 region of the 28S rRNA gene.

In order to confirm the phylogenetic relationships of Histoplasma capsulatum, the partial sequences of large subunit (28S) ribosomal gene (D1/D2 region) of 49 isolates were studied. The similarity values of the 49 isolates were more than 99.0% across 617 base pairs, however, the 49 isolates were divided into 9 groups. These 9 groups were independent of 3 varieties, var. capsulatum, var. farciminosum and var. duboisii. These results showed that analysis of the nucleotide sequence of the 28S rRNA gene was very effective for identification of H. capsulatum and that three varieties of H. capsulatum should be reclassified according to the phylogenetic relationship established from analysis of the D1/D2 region sequences.

Animals↗