Infection with filamentous fungi is a major cause of blindness. In this article, Leal et al. examined the role of reactive oxygen species in killing fungal infections in the eye. Here, mouse eyes are treated with pharmacologic inhibitors of thioredoxin following inoculation with Aspergillus (The fungi are genetically altered to appear red). The drug enhanced neutrophil-mediated killing, suggesting that drugs that target this pathway could be useful in treating fungal infections. Top, eyes treated with a thioredoxin inhibitor, bottom, control.
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.
Sixto M. Leal Jr., Chairut Vareechon, Susan Cowden, Brian A. Cobb, Jean-Paul Latgé, Michelle Momany, Eric Pearlman