Fungal antioxidant pathways promote survival against neutrophils during infection

Area of Science:

• Ophthalmology
• Mycology
• Immunology

Background:

• Filamentous fungi cause significant visual impairment globally.
• Fungal keratitis, an infection of the cornea, poses a serious threat to vision.

Purpose of the Study:

• To investigate the role of neutrophil NADPH oxidase in controlling fungal growth in the cornea.
• To identify fungal factors contributing to survival against neutrophil-mediated oxidative stress.
• To evaluate the therapeutic potential of targeting fungal antioxidant pathways.

Main Methods:

• Murine models of fungal keratitis and in vitro human neutrophils were used.
• Analysis of neutrophil oxidant production and antifungal activity.
• Utilized mutant Aspergillus fumigatus strains lacking specific genes.
• Assessed the effect of thioredoxin inhibition using PX-12 on fungal killing.

Main Results:

• Neutrophil NADPH oxidase is crucial for controlling Aspergillus and Fusarium fungal growth in the cornea.
• Neutrophil antifungal activity depends on CD18 but not dectin-1.
• Fungal genes Yap1, superoxide dismutases, and the thioredoxin pathway are vital for resisting neutrophil oxidation and in vivo survival.
• PX-12 treatment enhanced fungal susceptibility to oxidative and neutrophil-mediated killing, both in vitro and in vivo.

Conclusions:

• Host oxidative mechanisms and fungal antioxidant defenses are key regulators of fungal hyphal survival during infection.
• Targeting fungal antioxidant defenses with drugs like PX-12 presents a promising strategy for treating fungal keratitis.