Extracellular iron chelation in<i>Cryptococcus neoformans</i>

Jacobson, Eric S.; Petro, Michael J.

doi:10.1080/02681218780000501

Cited by 35 publications

(29 citation statements)

References 17 publications

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“…C. neoformans is not known to produce siderophores, and its mechanism of iron acquisition is uncertain (29,30). There is experimental evidence that C. neoformans can generate ferrous iron at the cell surface via reduction of ferric chelates, with the subsequent acquisition of the ferrous iron (30).…”

Section: Discussionmentioning

confidence: 99%

Chloroquine induces human mononuclear phagocytes to inhibit and kill Cryptococcus neoformans by a mechanism independent of iron deprivation.

Levitz¹,

Harrison²,

Tabuni³

et al. 1997

J. Clin. Invest.

119

123

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Infections due to Cryptococcus neoformans are common in AIDS patients. We investigated the effect of chloroquine, which raises the pH of phagolysosomes, on the anticryptococcal activity of mononuclear phagocytes. C. neoformans multiplied within monocyte-derived macrophages (MDM) in the absence of chloroquine but were killed with the addition of chloroquine. Ammonium chloride was also beneficial, suggesting that effects were mediated by alkalinizing the phagolysosome. Chloroquine inhibits growth of other intracellular pathogens by limiting iron availability. However, chloroquine-induced augmentation of MDM anticryptococcal activity was unaffected by iron nitriloacetate, demonstrating that chloroquine worked by a mechanism independent of iron deprivation. There was an inverse correlation between growth of C. neoformans in cell-free media and pH, suggesting that some of the effect of chloroquine on the anticryptococcal activity of MDM could be explained by relatively poor growth at higher pH. Chloroquine enhanced MDM anticryptococcal activity against all tested cryptococcal strains except for one large-capsule strain which was not phagocytosed. Positive effects of chloroquine were also seen in monocytes from both HIV-infected and -uninfected donors. Finally, chloroquine was therapeutic in experimental cryptococcosis in outbred and severe combined immunodeficient mice. Thus, chloroquine enhances the activity of mononuclear phagocytes against C. neoformans by ironindependent, pH-dependent mechanisms and is therapeutic in murine models of cryptococcosis. Chloroquine might have clinical utility for the prophylaxis and treatment of human cryptococcosis. (

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Section: Discussionmentioning

confidence: 99%

Chloroquine induces human mononuclear phagocytes to inhibit and kill Cryptococcus neoformans by a mechanism independent of iron deprivation.

Levitz¹,

Harrison²,

Tabuni³

et al. 1997

J. Clin. Invest.

119

123

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“…DFO is found to enhance the pathogenicity of Aspergillusfumigatus and of Cryptococcus neoformans but has no effect upon that of Candida albicans. Similarly, we and others found that the in vitro growth is increased by Fe.DFO in the first two (43) but not in the latter species (44). Radioiron uptake from "Fe.DFO, measured for A.fumigatus and C. albicans, was much lower (8.3-fold and 40.1-fold respectively) than for the clinical strain of R. microsporus.…”

Section: Discussionmentioning

confidence: 99%

Mucormycosis during deferoxamine therapy is a siderophore-mediated infection. In vitro and in vivo animal studies.

Boelaert¹,

Locht²,

Cutsem³

et al. 1993

J. Clin. Invest.

310

263

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“…However, cft1 and cfo1 mutants can obtain iron from siderophores, heme, and hemoglobin, thus indicating that another uptake pathway(s) is needed for these iron sources (10,11). The mechanisms of heme use have not been identified, but iron acquisition from siderophores is known to require specific transporters such as the ferrioxamine B transporter Sit1, although C. neoformans is unable to produce its own siderophores (15,16). The regulation of iron uptake mechanisms and sensing in C. neoformans is mediated by the master iron regulator Cir1, as well as several other regulatory proteins, including Nrg1, Rim101, and HapX (17,18,19,20,21).…”

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confidence: 99%

Cryptococcus neoformans Requires the ESCRT Protein Vps23 for Iron Acquisition from Heme, for Capsule Formation, and for Virulence

et al. 2013

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Iron availability is a key regulator of virulence factor elaboration in Cryptococcus neoformans, the causative agent of fungal meningoencephalitis in HIV/AIDS patients. In addition, iron is an essential nutrient for pathogen proliferation in mammalian hosts but little is known about the mechanisms of iron sensing and uptake in fungal pathogens that attack humans. In this study, we mutagenized C. neoformans by Agrobacterium-mediated T-DNA insertion and screened for mutants with reduced growth on heme as the sole iron source. Among 34 mutants, we identified a subset with insertions in the gene for the ESCRT-I (endosomal sorting complex required for transport) protein Vps23 that resulted in a growth defect on heme, presumably due to a defect in uptake via endocytosis or misregulation of iron acquisition from heme. Remarkably, vps23 mutants were also defective in the elaboration of the cell-associated capsular polysaccharide that is a major virulence factor, while overexpression of Vps23 resulted in cells with a slightly enlarged capsule. These phenotypes were mirrored by a virulence defect in the vps23 mutant in a mouse model of cryptococcosis and by hypervirulence of the overexpression strain. Overall, these results reveal an important role for trafficking via ESCRT functions in both heme uptake and capsule formation, and they further reinforce the connection between iron and virulence factor deployment in C. neoformans.

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Extracellular iron chelation inCryptococcus neoformans

Cited by 35 publications

References 17 publications

Chloroquine induces human mononuclear phagocytes to inhibit and kill Cryptococcus neoformans by a mechanism independent of iron deprivation.

Chloroquine induces human mononuclear phagocytes to inhibit and kill Cryptococcus neoformans by a mechanism independent of iron deprivation.

Mucormycosis during deferoxamine therapy is a siderophore-mediated infection. In vitro and in vivo animal studies.

Cryptococcus neoformans Requires the ESCRT Protein Vps23 for Iron Acquisition from Heme, for Capsule Formation, and for Virulence

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