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

Newman, Simon L.; Gootee, L; Stroobant, Vincent; Goot, H. van der; Boelaert, Johan R.

doi:10.1128/aac.39.8.1824

Cited by 33 publications

(19 citation statements)

References 46 publications

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“…As discussed earlier, Hc yeasts must procure intracellular iron to survive in human and murine M (28,54). Indeed, part of the mechanism by which IFN-␥ activates murine M antiHistoplasma activity is via the restriction of iron (33,55).…”

Section: Discussionmentioning

confidence: 99%

Human Macrophages Do Not Require Phagosome Acidification to Mediate Fungistatic/Fungicidal Activity againstHistoplasma capsulatum

Newman

Gootee

Hilty

et al. 2006

The Journal of Immunology

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Histoplasma capsulatum (Hc) is a facultative intracellular fungus that modulates the intraphagosomal environment to survive within macrophages (Mφ). In the present study, we sought to quantify the intraphagosomal pH under conditions in which Hc yeasts replicated or were killed. Human Mφ that had ingested both viable and heat-killed or fixed yeasts maintained an intraphagosomal pH of ∼6.4–6.5 over a period of several hours. These results were obtained using a fluorescent ratio technique and by electron microscopy using the 3-(2,4-dinitroanilo)-3′-amino-N-methyldipropylamine reagent. Mφ that had ingested Saccharomyces cerevisae, a nonpathogenic yeast that is rapidly killed and degraded by Mφ, also maintained an intraphagosomal pH of ∼6.5 over a period of several hours. Stimulation of human Mφ fungicidal activity by coculture with chloroquine or by adherence to type 1 collagen matrices was not reversed by bafilomycin, an inhibitor of the vacuolar ATPase. Human Mφ cultured in the presence of bafilomycin also completely degraded heat-killed Hc yeasts, whereas mouse peritoneal Mφ digestion of yeasts was completely reversed in the presence of bafilomycin. However, bafilomycin did not inhibit mouse Mφ fungistatic activity induced by IFN-γ. Thus, human Mφ do not require phagosomal acidification to kill and degrade Hc yeasts, whereas mouse Mφ do require acidification for fungicidal but not fungistatic activity.

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Section: Discussionmentioning

confidence: 99%

Human Macrophages Do Not Require Phagosome Acidification to Mediate Fungistatic/Fungicidal Activity againstHistoplasma capsulatum

Newman

Gootee

Hilty

et al. 2006

The Journal of Immunology

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“…Other authors demonstrated that both DEF and CHLOR suppressed the growth of Histoplasma capsulatum yeasts in human macrophages, the effect of DEF being reversed by HTF, and the effect of CHLOR reversed by FeNTA, but not by HTF (41). Several studies utilizing other drugs that interfere with iron metabolism, demonstrated the importance of iron on the multiplication and survival of Cryptococcus neoformans (34), Trypanosoma cruzi (28,36), L. pneumophila (6,8,18), H. capsulatum (29,42), Neisseria meningitidis (22), Mycobacterium tuberculosis (37), Mycobacterium avium (20), Listeria monocytogenes (1) and P. brasiliensis (14).…”

Section: Discussionmentioning

confidence: 99%

Chloroquine Inhibits Paracoccidioides brasiliensis Survival within Human Monocytes by Limiting the Availability of Intracellular Iron

Dias-Melício

Moreira

Calvi

et al. 2006

Microbiology and Immunology

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Paracoccidioidomycosis is a deep mycosis that is endemic in Latin America. This disease is caused by Paracoccidioides brasiliensis, a fungus that undergoes thermal dimorphism, developing as yeast at body temperature and as a mycelium at room temperature (16). This fungus causes natural infections by inhalation of conidia or mycelial elements. These conidia convert to the parasitic yeast form in the lungs of mice (39). Ingested conidia or yeast-forms of P. brasiliensis readily multiplied inside murine alveolar or peritoneal macrophages; however, if they were activated by cytokines, such as IFN-γ, the multiplication was limited and conidia or yeast cells were killed (5,10). Similarly, the interaction of human phagocytic cells and yeastform of P. brasiliensis was studied in vitro and yeast cells were readily ingested by monocytes or monocytederived macrophages. However, these cells allowed P. brasiliensis multiplication, unless they were activated with IFN-γ or culture supernatants from concanavalin-A-stimulated mononuclear cells, suggesting that this activation could be responsible for iron restriction and the consequent decrease in the survival of P. brasiliensis Abstract: The mechanisms used by Paracoccidioides brasiliensis (Pb 18) to survive into monocytes are not clear. Cellular iron metabolism is of critical importance to the growth of several intracellular pathogens, including P. brasiliensis, whose capacity to multiply in mononuclear phagocytes is dependent on the availability of intracellular iron. Chloroquine, by virtue of its basic properties, has been shown to prevent release of iron from holotransferrin by raising endocytic and lysosomal pH, and thereby interfering with normal iron metabolism. Then, in view of this, we have studied the effects of CHLOR on P. brasiliensis multiplication in human monocytes and its effect on the murine paracoccidioidomycosis. CHLOR induced human monocytes to kill P. brasiliensis. The effect of CHLOR was reversed by FeNTA, an iron compound that is soluble at neutral to alkaline pH, but not by holotransferrin, which releases iron only in an acidic environment. CHLOR treatment of Pb 18-infected BALB/c mice significantly reduced the viable fungi recovery from lungs, during three different periods of evaluation, in a dose-dependent manner. This study demonstrates that iron is of critical importance to the survival of P. brasiliensis yeasts within human monocytes and the CHLOR treatment in vitro induces Pb 18 yeast-killing by monocytes by restricting the availability of intracellular iron. Besides, the CHLOR treatment in vivo significantly reduces the number of organisms in the lungs of Pb-infected mice protecting them from several infections. Thus, CHLOR was effective in the treatment of murine paracoccidioidomycosis, suggesting the potential use of this drug in patients' treatment. Chloroquine Inhibits Paracoccidioides brasiliensis

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“…Most evidence that mycobacteria residing within human macrophages require a source of Fe has been indirect through studies with other intracellular pathogens in which the host cell Fe pool has been decreased or enhanced through the addition of Fe chelators or Fe supplementation of culture medium, respectively (5,37). Conclusions drawn from such approaches may be problematic since they mediate their effects through modulations of host cell physiology rather than by directly altering microbial access to Fe.…”

mentioning

confidence: 99%

Gallium Disrupts Iron Metabolism of Mycobacteria Residing within Human Macrophages

2000

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Mycobacterium tuberculosis and M. avium complex (MAC) enter and multiply within monocytes and macrophages in phagosomes. In vitro growth studies using standard culture media indicate that siderophoremediated iron (Fe) acquisition plays a critical role in the growth and metabolism of both M. tuberculosis and MAC. However, the applicability of such studies to conditions within the macrophage phagosome is unclear, due in part to the absence of experimental means to inhibit such a process. Based on the ability of gallium (Ga 3؉ ) to concentrate within mononuclear phagocytes and on evidence that Ga disrupts cellular Fe-dependent metabolic pathways by substituting for Fe 3؉ and failing to undergo redox cycling, we hypothesized that Ga could disrupt Fe acquisition and Fe-dependent metabolic pathways of mycobacteria. We find that Ga(NO 3 ) 3 and Ga-transferrin produce an Fe-reversible concentration-dependent growth inhibition of M. tuberculosis strains and MAC grown extracellularly and within human macrophages. Ga is bactericidal for M. tuberculosis growing extracellularly and within macrophages. Finally, we provide evidence that exogenously added Fe is acquired by intraphagosomal M. tuberculosis and that Ga inhibits this Fe acquisition. Thus, Ga(NO 3 ) 3 disruption of mycobacterial Fe metabolism may serve as an experimental means to study the mechanism of Fe acquisition by intracellular mycobacteria and the role of Fe in intracellular survival. Furthermore, given the inability of biological systems to discriminate between Ga and Fe, this approach could have broad applicability to the study of Fe metabolism of other intracellular pathogens.

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

Cited by 33 publications

References 46 publications

Human Macrophages Do Not Require Phagosome Acidification to Mediate Fungistatic/Fungicidal Activity againstHistoplasma capsulatum

Human Macrophages Do Not Require Phagosome Acidification to Mediate Fungistatic/Fungicidal Activity againstHistoplasma capsulatum

Chloroquine Inhibits Paracoccidioides brasiliensis Survival within Human Monocytes by Limiting the Availability of Intracellular Iron

Gallium Disrupts Iron Metabolism of Mycobacteria Residing within Human Macrophages

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