title: Targeting iron acquisition blocks infection with the fungal pathogens Aspergillus fumigatus and Fusarium oxysporum.
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.
authors.affiliation: Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Sixto M
authors.initials: SM
authors.lastname: Leal
authors.forename: Sanhita
authors.initials: S
authors.lastname: Roy
authors.forename: Chairut
authors.initials: C
authors.lastname: Vareechon
authors.forename: Steven deJesus
authors.initials: Sd
authors.lastname: Carrion
authors.forename: Heather
authors.initials: H
authors.lastname: Clark
authors.forename: Manuel S
authors.initials: MS
authors.lastname: Lopez-Berges
authors.forename: Antonio
authors.initials: A
authors.lastname: Di Pietro
authors.forename: Antonio
authors.initials: A
authors.lastname: diPietro
authors.forename: Marcus
authors.initials: M
authors.lastname: Schrettl
authors.forename: Nicola
authors.initials: N
authors.lastname: Beckmann
authors.forename: Bernhard
authors.initials: B
authors.lastname: Redl
authors.forename: Hubertus
authors.initials: H
authors.lastname: Haas
authors.forename: Eric
authors.initials: E
authors.lastname: Pearlman
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001228:Aspergillosis / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000517:prevention & control*; D001232:Aspergillus fumigatus / Q000187:drug effects* / Q000254:growth & development / Q000276:immunology / Q000378:metabolism; D001425:Bacterial Outer Membrane Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D003315:Cornea / Q000187:drug effects / Q000382:microbiology / Q000473:pathology; D015821:Eye Infections, Fungal / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000517:prevention & control*; D060585:Fusariosis / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000517:prevention & control*; D005670:Fusarium / Q000187:drug effects* / Q000254:growth & development / Q000276:immunology / Q000378:metabolism; D064451:Hepcidins / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000494:pharmacology / Q000627:therapeutic use; D037181:Lectins, C-Type / Q000378:metabolism; D054835:Lipocalin 1 / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D017262:Siderophores / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D013047:Specific Pathogen-Free Organisms; D000099181:Dectin-1
chemical_list: D000935:Antifungal Agents; D001425:Bacterial Outer Membrane Proteins; D064451:Hepcidins; D015850:Interleukin-6; D007501:Iron; D007502:Iron Chelating Agents; D037181:Lectins, C-Type; D054835:Lipocalin 1; D011956:Receptors, Cell Surface; D017262:Siderophores; D000099181:Dectin-1; C579599:Hamp protein, mouse; C518443:LCN1 protein, human; C577686:interleukin-6, mouse; C035902:siderophore receptors