Aspergillus fumigatus-Derived Extracellular Vesicles Mitigate Fungal Keratitis by Modulating the Immune Cell Function

Abstract

Fungal keratitis (FK) is a refractory global disease characterized by a high incidence of blindness and a lack of effective therapeutic options, and Aspergillus fumigatus (A. fumigatus, AF) is one of the most common causative fungi. This study aimed to investigate the role of extracellular vesicles (EVs) from A. fumigatus in the immune cell function and their protective role in A. fumigatus keratitis in order to explore their therapeutic potential. First, we isolated and characterized the EVs (AFderived EVs). In vitro, we stimulated RAW264.7 cells and polymorphonuclear cells with AF-derived EVs. The expression levels of inflammatory factors increased in both immune cells along with an M1 polarization variation of RAW264.7 cells. After being incubated with AF-derived EVs, both immune cells exhibited an increased conidia-phagocytic index and a decreased conidia survival rate. In vivo, we injected EVs subconjunctivally on mice resulting in a heightened production of secretory immunoglobulin A (sIgA) in tear fluid. By the injection of EVs on mice in advance, a significant reduction in severity of A. fumigatus FK was witnessed by lower clinical scores, inflammatory appearances, and mitigated fungal load. Collectively, these results positioned AF-derived EVs as a promising and innovative immune therapy for combating FK, while also providing a platform for further investigation into developing an optimal formulation for modulating inflammation in the context of FK.