1. Targeting iron acquisition blocks infection with the fungal pathogens Aspergillus fumigatus and Fusarium oxysporum.
- Author
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Leal SM Jr, Roy S, Vareechon C, Carrion Sd, Clark H, Lopez-Berges MS, Di Pietro A, Schrettl M, Beckmann N, Redl B, Haas H, and Pearlman E
- Subjects
- Animals, Antifungal Agents pharmacology, Aspergillosis immunology, Aspergillosis metabolism, Aspergillosis microbiology, Aspergillus fumigatus growth & development, Aspergillus fumigatus immunology, Aspergillus fumigatus metabolism, Bacterial Outer Membrane Proteins genetics, Bacterial Outer Membrane Proteins metabolism, Cells, Cultured, Cornea drug effects, Cornea microbiology, Cornea pathology, Eye Infections, Fungal immunology, Eye Infections, Fungal metabolism, Eye Infections, Fungal microbiology, Fusariosis immunology, Fusariosis metabolism, Fusariosis microbiology, Fusarium growth & development, Fusarium immunology, Fusarium metabolism, Hepcidins metabolism, Humans, Interleukin-6 genetics, Interleukin-6 metabolism, Iron Chelating Agents pharmacology, Iron Chelating Agents therapeutic use, Lectins, C-Type metabolism, Lipocalin 1 metabolism, Lipocalin 1 pharmacology, Lipocalin 1 therapeutic use, Mice, Mice, Inbred C57BL, Mice, Knockout, Mutation, Neutrophils cytology, Neutrophils drug effects, Neutrophils immunology, Neutrophils metabolism, Receptors, Cell Surface genetics, Receptors, Cell Surface metabolism, Siderophores antagonists & inhibitors, Siderophores biosynthesis, Siderophores metabolism, Specific Pathogen-Free Organisms, Antifungal Agents therapeutic use, Aspergillosis prevention & control, Aspergillus fumigatus drug effects, Eye Infections, Fungal prevention & control, Fusariosis prevention & control, Fusarium drug effects, Iron metabolism
- 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.
- Published
- 2013
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