Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antifungal Agents / pharmacology
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Antifungal Agents / therapeutic use*
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Aspergillosis / immunology
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Aspergillosis / metabolism
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Aspergillosis / microbiology
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Aspergillosis / prevention & control*
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Aspergillus fumigatus / drug effects*
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Aspergillus fumigatus / growth & development
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Aspergillus fumigatus / immunology
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Aspergillus fumigatus / metabolism
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Bacterial Outer Membrane Proteins / genetics
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Bacterial Outer Membrane Proteins / metabolism
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Cells, Cultured
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Cornea / drug effects
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Cornea / microbiology
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Cornea / pathology
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Eye Infections, Fungal / immunology
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Eye Infections, Fungal / metabolism
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Eye Infections, Fungal / microbiology
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Eye Infections, Fungal / prevention & control*
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Fusariosis / immunology
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Fusariosis / metabolism
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Fusariosis / microbiology
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Fusariosis / prevention & control*
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Fusarium / drug effects*
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Fusarium / growth & development
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Fusarium / immunology
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Fusarium / metabolism
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Hepcidins / metabolism
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Humans
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Interleukin-6 / genetics
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Interleukin-6 / metabolism
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Iron / metabolism*
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Iron Chelating Agents / pharmacology
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Iron Chelating Agents / therapeutic use
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Lectins, C-Type / metabolism
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Lipocalin 1 / metabolism
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Lipocalin 1 / pharmacology
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Lipocalin 1 / therapeutic use
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mutation
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Neutrophils / cytology
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Neutrophils / drug effects
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Neutrophils / immunology
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Neutrophils / metabolism
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Receptors, Cell Surface / genetics
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Receptors, Cell Surface / metabolism
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Siderophores / antagonists & inhibitors
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Siderophores / biosynthesis
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Siderophores / metabolism
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Specific Pathogen-Free Organisms
Substances
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Antifungal Agents
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Bacterial Outer Membrane Proteins
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Hamp protein, mouse
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Hepcidins
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Interleukin-6
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Iron Chelating Agents
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LCN1 protein, human
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Lectins, C-Type
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Lipocalin 1
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Receptors, Cell Surface
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Siderophores
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dectin 1
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interleukin-6, mouse
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siderophore receptors
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Iron