Iron uptake from ferrioxamine and from ferrirhizoferrin by germinating spores of rhizopus microsporus

Locht, M. de; Boelaert, Johan R.; Schneider, Yves‐Jacques

doi:10.1016/0006-2952(94)90314-x

Cited by 114 publications

(115 citation statements)

References 14 publications

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“…Interestingly, patients being treated for iron overload with desferroxamine, a siderophore made by Streptomyces, are at increased risk for mucormycosis (56). This may be explained by the observation that Rhizopus microsporus, one of the causes of mucormycosis, is able to acquire iron from the iron-chelated form of the bacterial siderophore, ferroxamine (57). Similarly, Saccharomyces cerevisiae is able to take up and use iron from ferroxamine (58).…”

Section: Discussionmentioning

confidence: 99%

Human Polymorphonuclear Leukocytes Inhibit Aspergillus fumigatus Conidial Growth by Lactoferrin-Mediated Iron Depletion

Zarember

Sugui

Chang

et al. 2007

The Journal of Immunology

173

137

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Aspergillus fumigatus, a common mold, rarely infects humans, except during prolonged neutropenia or in cases of chronic granulomatous disease (CGD), a primary immunodeficiency caused by mutations in the NADPH oxidase that normally produces fungicidal reactive oxygen species. Filamentous hyphae of Aspergillus are killed by normal, but not CGD polymorphonuclear leukocytes (PMN); however, the few studies on PMN-mediated host defenses against infectious conidia (spores) of this organism have yielded conflicting results, some showing that PMN do not inhibit conidial growth, with others showing that they do, most likely using reactive oxygen species. Given that CGD patients are exposed daily to hundreds of viable A. fumigatus conidia, yet considerable numbers of them survive years without infection, we reasoned that PMN use ROS-independent mechanisms to combat Aspergillus. We show that human PMN from both normal controls and CGD patients are equipotent at arresting the growth of Aspergillus conidia in vitro, indicating the presence of a reactive oxygen species-independent factor(s). Cell-free supernatants of degranulated normal and CGD neutrophils both suppressed fungal growth and were found to be rich in lactoferrin, an abundant PMN secondary granule protein. Purified iron-poor lactoferrin at concentrations occurring in PMN supernatants (and reported in human mucosal secretions in vivo) decreased fungal growth, whereas saturation of lactoferrin or PMN supernatants with iron, or testing in the presence of excess iron in the form of ferritin, completely abolished activity against conidia. These results demonstrate that PMN lactoferrin sequestration of iron is important for host defense against Aspergillus.

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Section: Discussionmentioning

confidence: 99%

Human Polymorphonuclear Leukocytes Inhibit Aspergillus fumigatus Conidial Growth by Lactoferrin-Mediated Iron Depletion

Zarember

Sugui

Chang

et al. 2007

The Journal of Immunology

173

137

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“…Based on this role of iron sequestration in innate immunity, recent interest has been generated in the possibility of utilizing iron chelation therapy as a treatment for infectious diseases. Mucormycosis is a particularly promising target for iron chelation therapy given the exceptional iron requirement for growth and pathogenicity of Mucorales (12)(13)(14)(15). For example, it is likely that diabetic ketoacidosis and other systemic acidoses predispose patients to developing mucormycosis by inducing dissociation of iron from sequestering proteins, resulting in elevated available serum iron (2,16,17).…”

Section: Introductionmentioning

confidence: 99%

“…However, while deferoxamine is an iron chelator from the perspective of the human host, it serves as a xenosiderophore to Mucorales, which are able to specifically bind to deferoxamineiron complexes, strip the iron from the chelator through an energy-dependent reductive process, and facilitate iron uptake (12,18). Furthermore, administration of deferoxamine worsens survival of animals with mucormycosis (12)(13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

The iron chelator deferasirox protects mice from mucormycosis through iron starvation

Ibrahim¹,

Gebermariam²,

Fu³

et al. 2007

J. Clin. Invest.

290

274

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Mucormycosis causes mortality in at least 50% of cases despite current first-line therapies. Clinical and animal data indicate that the presence of elevated available serum iron predisposes the host to mucormycosis. Here we demonstrate that deferasirox, an iron chelator recently approved for use in humans by the US FDA, is a highly effective treatment for mucormycosis. Deferasirox effectively chelated iron from Rhizopus oryzae and demonstrated cidal activity in vitro against 28 of 29 clinical isolates of Mucorales at concentrations well below clinically achievable serum levels. When administered to diabetic ketoacidotic or neutropenic mice with mucormycosis, deferasirox significantly improved survival and decreased tissue fungal burden, with an efficacy similar to that of liposomal amphotericin B. Deferasirox treatment also enhanced the host inflammatory response to mucormycosis. Most importantly, deferasirox synergistically improved survival and reduced tissue fungal burden when combined with liposomal amphotericin B. These data support clinical investigation of adjunctive deferasirox therapy to improve the poor outcomes of mucormycosis with current therapy. As iron availability is integral to the pathogenesis of other infections (e.g., tuberculosis, malaria), broader investigation of deferasirox as an antiinfective treatment is warranted.

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“…Iron is also an important factor in fungal infections. For example, treatment of dialysis patients with the iron-chelating drug desferrioxamine B is a risk factor for zygomycoses, because iron bound to desferrioxamine is efficiently used as an iron source by some species of zygomycetes (1,11).…”

mentioning

confidence: 99%

The Aspergillus fumigatus Siderophore Biosynthetic Gene sidA , Encoding l -Ornithine N ⁵ -Oxygenase, Is Required for Virulence

et al. 2005

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Aspergillus fumigatus is the leading cause of invasive mold infection and is a serious problem in immunocompromised populations worldwide. We have previously shown that survival of A. fumigatus in serum may be related to secretion of siderophores. In this study, we identified and characterized the sidA gene of A. fumigatus, which encodes L-ornithine N 5 -oxygenase, the first committed step in hydroxamate siderophore biosynthesis. A. fumigatus sidA codes for a protein of 501 amino acids with significant homology to other fungal L-ornithine N 5 -oxygenases. A stable ⌬sidA strain was created by deletion of A. fumigatus sidA. This strain was unable to synthesize the siderophores N,N؆,Nٟ-triacetylfusarinine C (TAF) and ferricrocin. Growth of the ⌬sidA strain was the same as that of the wild type in rich media; however, the ⌬sidA strain was unable to grow in low-iron defined media or media containing 10% human serum unless supplemented with TAF or ferricrocin. No significant differences in ferric reduction activities were observed between the parental strain and the ⌬sidA strain, indicating that blocking siderophore secretion did not result in upregulation of this pathway. Unlike the parental strain, the ⌬sidA strain was unable to remove iron from human transferrin. A rescued strain (⌬sidA ؉ sidA) was constructed; it produced siderophores and had the same growth as the wild type on iron-limited media. Unlike the wild-type and rescued strains, the ⌬sidA strain was avirulent in a mouse model of invasive aspergillosis, indicating that sidA is necessary for A. fumigatus virulence.

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Iron uptake from ferrioxamine and from ferrirhizoferrin by germinating spores of rhizopus microsporus

Cited by 114 publications

References 14 publications

Human Polymorphonuclear Leukocytes Inhibit Aspergillus fumigatus Conidial Growth by Lactoferrin-Mediated Iron Depletion

Human Polymorphonuclear Leukocytes Inhibit Aspergillus fumigatus Conidial Growth by Lactoferrin-Mediated Iron Depletion

The iron chelator deferasirox protects mice from mucormycosis through iron starvation

The Aspergillus fumigatus Siderophore Biosynthetic Gene sidA , Encoding l -Ornithine N ⁵ -Oxygenase, Is Required for Virulence

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Iron uptake from ferrioxamine and from ferrirhizoferrin by germinating spores of rhizopus microsporus

Cited by 114 publications

References 14 publications

Human Polymorphonuclear Leukocytes Inhibit Aspergillus fumigatus Conidial Growth by Lactoferrin-Mediated Iron Depletion

Human Polymorphonuclear Leukocytes Inhibit Aspergillus fumigatus Conidial Growth by Lactoferrin-Mediated Iron Depletion

The iron chelator deferasirox protects mice from mucormycosis through iron starvation

The Aspergillus fumigatus Siderophore Biosynthetic Gene sidA , Encoding l -Ornithine N 5 -Oxygenase, Is Required for Virulence

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The Aspergillus fumigatus Siderophore Biosynthetic Gene sidA , Encoding l -Ornithine N ⁵ -Oxygenase, Is Required for Virulence