Fungal antioxidant pathways promote survival against neutrophils during infection.
Filamentous fungi are a common cause of blindness and visual impairment worldwide. Using both murine model systems and in vitro human neutrophils, we found that NADPH oxidase produced by neutrophils was essential to control the growth of Aspergillus and Fusarium fungi in the cornea. We demonstrated that neutrophil oxidant production and antifungal activity are dependent on CD18, but not on the β-glucan receptor dectin-1. We used mutant A. fumigatus strains to show that the reactive oxygen species-sensing transcription factor Yap1, superoxide dismutases, and the Yap1-regulated thioredoxin antioxidant pathway are each required for protection against neutrophil-mediated oxidation of hyphae as well as optimal survival of fungal hyphae in vivo. We also demonstrated that thioredoxin inhibition using the anticancer drug PX-12 increased the sensitivity of fungal hyphae to both H2O2- and neutrophil-mediated killing in vitro. Additionally, topical application of PX-12 significantly enhanced neutrophil-mediated fungal killing in infected mouse corneas. Cumulatively, our data reveal critical host oxidative and fungal anti-oxidative mediators that regulate hyphal survival during infection. Further, these findings also indicate that targeting fungal anti-oxidative defenses via PX-12 may represent an efficacious strategy for treating fungal infections.
Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH 44106, USA.
Sixto M
SM
Leal
Chairut
C
Vareechon
Susan
S
Cowden
Brian A
BA
Cobb
Jean-Paul
JP
Latgé
Michelle
M
Momany
Eric
E
Pearlman
D000818:Animals; D000975:Antioxidants / Q000378:metabolism* / Q000502:physiology; D001228:Aspergillosis / Q000276:immunology / Q000382:microbiology* / Q000473:pathology; D001231:Aspergillus flavus / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D001232:Aspergillus fumigatus / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D018821:CD18 Antigens / Q000378:metabolism; D002478:Cells, Cultured; D003315:Cornea / Q000382:microbiology / Q000473:pathology; D004789:Enzyme Activation; D005656:Fungal Proteins / Q000378:metabolism / Q000502:physiology; D060585:Fusariosis / Q000276:immunology / Q000382:microbiology* / Q000473:pathology; D005670:Fusarium / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D054884:Host-Pathogen Interactions; D006801:Humans; D007634:Keratitis / Q000276:immunology / Q000382:microbiology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050296:Microbial Viability; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000201:enzymology / Q000276:immunology* / Q000382:microbiology; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D018384:Oxidative Stress; D009195:Peroxidase / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism / Q000502:physiology; D013879:Thioredoxins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology
D000975:Antioxidants; D018821:CD18 Antigens; D005656:Fungal Proteins; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D009569:Nitric Oxide; D013879:Thioredoxins; D009195:Peroxidase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D013482:Superoxide Dismutase; D019255:NADPH Oxidases