Targeting iron acquisition blocks infection with the fungal pathogens Aspergillus fumigatus and Fusarium oxysporum.

Filamentous fungi are an important cause of pulmonary and systemic morbidity and mortality, and also cause corneal blindness and visual impairment worldwide. Utilizing in vitro neutrophil killing assays and a model of fungal infection of the cornea, we demonstrated that Dectin-1 dependent IL-6 produ...

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Main Authors: Sixto M Leal, Sanhita Roy, Chairut Vareechon, Steven deJesus Carrion, Heather Clark, Manuel S Lopez-Berges, Antonio Di Pietro, Marcus Schrettl, Nicola Beckmann, Bernhard Redl, Hubertus Haas, Eric Pearlman
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2013-01-01
Series:PLoS Pathogens
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23853581/?tool=EBI
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author Sixto M Leal
Sanhita Roy
Chairut Vareechon
Steven deJesus Carrion
Heather Clark
Manuel S Lopez-Berges
Antonio Di Pietro
Marcus Schrettl
Nicola Beckmann
Bernhard Redl
Hubertus Haas
Eric Pearlman
author_facet Sixto M Leal
Sanhita Roy
Chairut Vareechon
Steven deJesus Carrion
Heather Clark
Manuel S Lopez-Berges
Antonio Di Pietro
Marcus Schrettl
Nicola Beckmann
Bernhard Redl
Hubertus Haas
Eric Pearlman
author_sort Sixto M Leal
collection DOAJ
description Filamentous fungi are an important cause of pulmonary and systemic morbidity and mortality, and also cause corneal blindness and visual impairment worldwide. Utilizing in vitro neutrophil killing assays and a model of fungal infection of the cornea, we demonstrated that Dectin-1 dependent IL-6 production regulates expression of iron chelators, heme and siderophore binding proteins and hepcidin in infected mice. In addition, we show that human neutrophils synthesize lipocalin-1, which sequesters fungal siderophores, and that topical lipocalin-1 or lactoferrin restricts fungal growth in vivo. Conversely, we show that exogenous iron or the xenosiderophore deferroxamine enhances fungal growth in infected mice. By examining mutant Aspergillus and Fusarium strains, we found that fungal transcriptional responses to low iron levels and extracellular siderophores are essential for fungal growth during infection. Further, we showed that targeting fungal iron acquisition or siderophore biosynthesis by topical application of iron chelators or statins reduces fungal growth in the cornea by 60% and that dual therapy with the iron chelator deferiprone and statins further restricts fungal growth by 75%. Together, these studies identify specific host iron-chelating and fungal iron-acquisition mediators that regulate fungal growth, and demonstrate that therapeutic inhibition of fungal iron acquisition can be utilized to treat topical fungal infections.
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spelling doaj.art-d68745bffe404aedb98f88c87cd843dd2022-12-21T22:42:41ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742013-01-0197e100343610.1371/journal.ppat.1003436Targeting iron acquisition blocks infection with the fungal pathogens Aspergillus fumigatus and Fusarium oxysporum.Sixto M LealSanhita RoyChairut VareechonSteven deJesus CarrionHeather ClarkManuel S Lopez-BergesAntonio Di PietroMarcus SchrettlNicola BeckmannBernhard RedlHubertus HaasEric PearlmanFilamentous fungi are an important cause of pulmonary and systemic morbidity and mortality, and also cause corneal blindness and visual impairment worldwide. Utilizing in vitro neutrophil killing assays and a model of fungal infection of the cornea, we demonstrated that Dectin-1 dependent IL-6 production regulates expression of iron chelators, heme and siderophore binding proteins and hepcidin in infected mice. In addition, we show that human neutrophils synthesize lipocalin-1, which sequesters fungal siderophores, and that topical lipocalin-1 or lactoferrin restricts fungal growth in vivo. Conversely, we show that exogenous iron or the xenosiderophore deferroxamine enhances fungal growth in infected mice. By examining mutant Aspergillus and Fusarium strains, we found that fungal transcriptional responses to low iron levels and extracellular siderophores are essential for fungal growth during infection. Further, we showed that targeting fungal iron acquisition or siderophore biosynthesis by topical application of iron chelators or statins reduces fungal growth in the cornea by 60% and that dual therapy with the iron chelator deferiprone and statins further restricts fungal growth by 75%. Together, these studies identify specific host iron-chelating and fungal iron-acquisition mediators that regulate fungal growth, and demonstrate that therapeutic inhibition of fungal iron acquisition can be utilized to treat topical fungal infections.https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23853581/?tool=EBI
spellingShingle Sixto M Leal
Sanhita Roy
Chairut Vareechon
Steven deJesus Carrion
Heather Clark
Manuel S Lopez-Berges
Antonio Di Pietro
Marcus Schrettl
Nicola Beckmann
Bernhard Redl
Hubertus Haas
Eric Pearlman
Targeting iron acquisition blocks infection with the fungal pathogens Aspergillus fumigatus and Fusarium oxysporum.
PLoS Pathogens
title Targeting iron acquisition blocks infection with the fungal pathogens Aspergillus fumigatus and Fusarium oxysporum.
title_full Targeting iron acquisition blocks infection with the fungal pathogens Aspergillus fumigatus and Fusarium oxysporum.
title_fullStr Targeting iron acquisition blocks infection with the fungal pathogens Aspergillus fumigatus and Fusarium oxysporum.
title_full_unstemmed Targeting iron acquisition blocks infection with the fungal pathogens Aspergillus fumigatus and Fusarium oxysporum.
title_short Targeting iron acquisition blocks infection with the fungal pathogens Aspergillus fumigatus and Fusarium oxysporum.
title_sort targeting iron acquisition blocks infection with the fungal pathogens aspergillus fumigatus and fusarium oxysporum
url https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23853581/?tool=EBI
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