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...
Guardado en:
| Autores principales: | , , , , , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Public Library of Science (PLoS)
2013
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/d68745bffe404aedb98f88c87cd843dd |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:d68745bffe404aedb98f88c87cd843dd |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:d68745bffe404aedb98f88c87cd843dd2021-11-18T06:05:25ZTargeting iron acquisition blocks infection with the fungal pathogens Aspergillus fumigatus and Fusarium oxysporum.1553-73661553-737410.1371/journal.ppat.1003436https://doaj.org/article/d68745bffe404aedb98f88c87cd843dd2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23853581/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Filamentous 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.Sixto M LealSanhita RoyChairut VareechonSteven deJesus CarrionHeather ClarkManuel S Lopez-BergesAntonio Di PietroMarcus SchrettlNicola BeckmannBernhard RedlHubertus HaasEric PearlmanPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 9, Iss 7, p e1003436 (2013) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 |
| spellingShingle |
Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 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. |
| 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. |
| format |
article |
| 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 |
| title |
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_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_sort |
targeting iron acquisition blocks infection with the fungal pathogens aspergillus fumigatus and fusarium oxysporum. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2013 |
| url |
https://doaj.org/article/d68745bffe404aedb98f88c87cd843dd |
| work_keys_str_mv |
AT sixtomleal targetingironacquisitionblocksinfectionwiththefungalpathogensaspergillusfumigatusandfusariumoxysporum AT sanhitaroy targetingironacquisitionblocksinfectionwiththefungalpathogensaspergillusfumigatusandfusariumoxysporum AT chairutvareechon targetingironacquisitionblocksinfectionwiththefungalpathogensaspergillusfumigatusandfusariumoxysporum AT stevendejesuscarrion targetingironacquisitionblocksinfectionwiththefungalpathogensaspergillusfumigatusandfusariumoxysporum AT heatherclark targetingironacquisitionblocksinfectionwiththefungalpathogensaspergillusfumigatusandfusariumoxysporum AT manuelslopezberges targetingironacquisitionblocksinfectionwiththefungalpathogensaspergillusfumigatusandfusariumoxysporum AT antoniodipietro targetingironacquisitionblocksinfectionwiththefungalpathogensaspergillusfumigatusandfusariumoxysporum AT marcusschrettl targetingironacquisitionblocksinfectionwiththefungalpathogensaspergillusfumigatusandfusariumoxysporum AT nicolabeckmann targetingironacquisitionblocksinfectionwiththefungalpathogensaspergillusfumigatusandfusariumoxysporum AT bernhardredl targetingironacquisitionblocksinfectionwiththefungalpathogensaspergillusfumigatusandfusariumoxysporum AT hubertushaas targetingironacquisitionblocksinfectionwiththefungalpathogensaspergillusfumigatusandfusariumoxysporum AT ericpearlman targetingironacquisitionblocksinfectionwiththefungalpathogensaspergillusfumigatusandfusariumoxysporum |
| _version_ |
1718424635139162112 |