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

Newman, Simon L.; Gootee, L; Gabay, Joëlle E.

doi:10.1172/jci116630

Cited by 67 publications

(70 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These results are consistent with previous studies that have suggested that Histoplasma yeasts are impervious to the effects of toxic oxygen metabolites generated by human and murine Mø (3,16,34,52). The data also are consistent with the fact that all of the very potent fungistatic activity exhibited by human neutrophils against H. capsulatum yeasts is mediated by the azurophil granules, and the production of toxic oxygen metabolites is not required for neutrophil fungistatic activity (38).…”

Section: Discussionsupporting

confidence: 83%

“…In vitro studies in human Mø (3,38,43) and in murine Mø (16,52) demonstrate that H. capsulatum yeasts are inherently resistant to toxic oxygen metabolites of the respiratory burst. Thus, although the respiratory burst may be stimulated during phagocytosis, H. capsulatum yeasts readily replicate in these cells.…”

Section: Resultsmentioning

confidence: 99%

“…Histoplasma yeasts have adapted to survive within human Mø by inhibiting phagosome-lysosome fusion (PL-fusion) (39) and controlling intraphagosomal pH (9,48). The fungus also appears to be inherently resistant to toxic oxygen metabolites of the respiratory burst (3,38,43).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Human Dendritic Cell Activity againstHistoplasma capsulatumIs Mediated via Phagolysosomal Fusion

et al. 2005

View full text Add to dashboard Cite

Histoplasma capsulatum is a fungal pathogen that requires the induction of cell-mediated immunity (CMI) for host survival. We have demonstrated that human dendritic cells (DC) phagocytose H. capsulatum yeasts and, unlike human macrophages (Mø) that are permissive for intracellular growth, DC killed and degraded the fungus. In the present study, we sought to determine whether the mechanism(s) by which DC kill Histoplasma is via lysosomal hydrolases, via the production of toxic oxygen metabolites, or both. Phagosome-lysosome fusion (PL-fusion) was quantified by using fluorescein isothiocyanate-dextran and phase and fluorescence microscopy and by electron microscopy with horseradish peroxidase colloidal gold to label lysosomes. Unlike M, Histoplasma-infected DC exhibited marked PL-fusion. The addition of suramin to Histoplasma-infected DC inhibited PL-fusion and DC fungicidal activity. Incubation of Histoplasma-infected DC at 18°C also concomitantly reduced PL-fusion and decreased the capacity of DC to kill and degrade H. capsulatum yeasts. Further, culture of Histoplasma-infected DC in the presence of bafilomycin, an inhibitor of the vacuolar ATPase, did not block DC anti-Histoplasma activity, indicating that phagosome acidification was not required for lysosome enzyme activity. In contrast, culture of Histoplasma-infected DC in the presence of inhibitors of the respiratory burst or inhibitors of NO synthase had little to no effect on DC fungicidal activity. These data suggest that the major mechanism by which human DC mediate anti-Histoplasma activity is through the exposure of yeasts to DC lysosomal hydrolases. Thus, DC can override one of the strategies used by H. capsulatum yeasts to survive intracellularly within Mø.

show abstract

Section: Discussionsupporting

confidence: 83%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Human Dendritic Cell Activity againstHistoplasma capsulatumIs Mediated via Phagolysosomal Fusion

et al. 2005

View full text Add to dashboard Cite

show abstract

“…Quantitation of fungistatic activity against H. capsulatum yeasts. The fungistatic activity of the various azurophil granule components was quantified by the incorporation of [ 3 H]leucine into remaining viable yeasts (23). Viable H. capsulatum yeasts (5 ϫ 10 3 in 0.1 ml) were added to the wells of a 96-well tissue culture plate and were incubated with 0.1 ml of various concentrations of individual components of neutrophil azurophil granules.…”

Section: Methodsmentioning

confidence: 99%

Identification of Constituents of Human Neutrophil Azurophil Granules That Mediate Fungistasis againstHistoplasma capsulatum

et al. 2000

View full text Add to dashboard Cite

Previously we demonstrated that human neutrophils mediate potent and long-lasting fungistasis against Histoplasma capsulatum yeasts and that all of the fungistatic activity resides in the azurophil granules. In the present study, specific azurophil granule constituents with fungistatic activity were identified by incubation with H. capsulatum yeasts for 24 h and by quantifying the subsequent growth of yeasts via the incorporation of [ 3 H]leucine. Human neutrophil defensins HNP-1, HNP-2, and HNP-3 inhibited the growth of H. capsulatum yeasts in a concentration-dependent manner with maximum inhibition at 8 g/ml. At a concentration of 4 g/ml, all possible paired combinations of defensins exhibited additive fungistatic activity against H. capsulatum yeasts. Cathepsin G and bactericidal-permeability-increasing protein (BPI) also mediated fungistasis against H. capsulatum in a concentration-dependent manner. The fungistatic activities of combinations of cathepsin G and BPI were additive, as were those of combinations of cathepsin G or BPI with HNP-1, HNP-2, and HNP-3. Lysozyme and elastase exhibited modest antifungal activity, and azurocidin and proteinase 3 exhibited no significant fungistasis against H. capsulatum yeasts. Thus, defensins, cathepsin G, and BPI are the major anti-H. capsulatum effector molecules in the azurophil granules of human neutrophils.Histoplasma capsulatum is a dimorphic fungal pathogen of worldwide importance that causes a broad spectrum of disease activity. The course of H. capsulatum infection is mild in most immunocompetent individuals, but progressive disseminated infections occur in individuals immunocompromised by hematologic malignancies (6,25,30) or cytotoxic therapy (16,32,33) or in individuals infected with human immunodeficiency virus (15,20,31).Infection with H. capsulatum is acquired by inhalation of microconidia into the terminal bronchioles and alveoli of the lung. Inhaled microconidia subsequently convert into yeasts that are responsible for the pathogenesis of histoplasmosis (17). H. capsulatum yeasts are phagocytized by alveolar macrophages (M), within which they multiply (2, 7). Dividing yeasts destroy the alveolar M, and subsequently the yeasts are ingested by other resident alveolar M and by inflammatory phagocytes recruited to the locus of infection. Repetition of this cycle results in spread of infection to hilar lymph nodes and to other organs during the acute phase of primary histoplasmosis. Subsequently, the maturation of specific cell-mediated immunity against H. capsulatum activates M to halt yeast proliferation with gradual resolution of the disease process in immunocompetent hosts (7,22).The role of polymorphonuclear neutrophils (PMNs) in the cell-mediated immune response against H. capsulatum is unclear (7). However, even the earliest studies in a murine model of histoplasmosis described PMNs as being the predominant inflammatory cell type in the lungs during the first 36 h after intranasal inoculation with H. capsulatum macroconidia. In these studies the PMNs ...

show abstract

“…The role of cathepsins in host defenses to this fungus is poorly understood. Cathepsin G inhibits, but does not kill, H. capsulatum yeast cells (71). Thus, it seems unlikely that Boc-D-FMK subverts protective immunity by a direct alteration of cathepsin activity.…”

Section: Figurementioning

confidence: 99%

Apoptosis modulates protective immunity to the pathogenic fungus Histoplasma capsulatum

Allen

Deepe²

2005

Journal of Clinical Investigation

View full text Add to dashboard Cite

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-α-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.

show abstract

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

Cited by 67 publications

References 45 publications

Human Dendritic Cell Activity againstHistoplasma capsulatumIs Mediated via Phagolysosomal Fusion

Human Dendritic Cell Activity againstHistoplasma capsulatumIs Mediated via Phagolysosomal Fusion

Identification of Constituents of Human Neutrophil Azurophil Granules That Mediate Fungistasis againstHistoplasma capsulatum

Apoptosis modulates protective immunity to the pathogenic fungus Histoplasma capsulatum

Contact Info

Product

Resources

About