Distinct Roles for Dectin-1 and TLR4 in the Pathogenesis of Aspergillus fumigatus Keratitis

PLoS Pathogens

Michelle Momany¹  Mahmoud A. Ghannoum²  Sixto M. Leal Jr²  Susan Cowden³  Yen-Cheng Hsia⁴  Eric Pearlman⁴ 

[1] Center for Medical Mycology, Case Western Reserve University, Cleveland, Ohio, United States of America;Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, Ohio, United States of America;Department of Pathology, Case Western Reserve University, Cleveland, Ohio, United States of America;Department of Plant Biology, University of Georgia, Athens, Georgia, United States of America

关键词: Cornea;    Aspergillus fumigatus;    Aspergillus;    Macrophages;    Keratitis;    Mouse models;    Fungal diseases;    Neutrophils;   

DOI  :  10.1371/journal.ppat.1000976

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Aspergillus species are a major worldwide cause of corneal ulcers, resulting in visual impairment and blindness in immunocompetent individuals. To enhance our understanding of the pathogenesis of Aspergillus keratitis, we developed a murine model in which red fluorescent protein (RFP)-expressing A. fumigatus (Af293.1RFP) conidia are injected into the corneal stroma, and disease progression and fungal survival are tracked over time. Using Mafia mice in which c-fms expressing macrophages and dendritic cells can be induced to undergo apoptosis, we demonstrated that the presence of resident corneal macrophages is essential for production of IL-1β and CXCL1/KC, and for recruitment of neutrophils and mononuclear cells into the corneal stroma. We found that β-glucan was highly expressed on germinating conidia and hyphae in the cornea stroma, and that both Dectin-1 and phospho-Syk were up-regulated in infected corneas. Additionally, we show that infected Dectin-1−/− corneas have impaired IL-1β and CXCL1/KC production, resulting in diminished cellular infiltration and fungal clearance compared with control mice, especially during infection with clinical isolates expressing high β-glucan. In contrast to Dectin 1−/− mice, cellular infiltration into infected TLR2−/−, TLR4−/−, and MD-2−/− mice corneas was unimpaired, indicating no role for these receptors in cell recruitment; however, fungal killing was significantly reduced in TLR4−/− mice, but not TLR2−/− or MD-2−/− mice. We also found that TRIF−/− and TIRAP−/− mice exhibited no fungal-killing defects, but that MyD88−/− and IL-1R1−/− mice were unable to regulate fungal growth. In conclusion, these data are consistent with a model in which β-glucan on A.fumigatus germinating conidia activates Dectin-1 on corneal macrophages to produce IL-1β, and CXCL1, which together with IL-1R1/MyD88-dependent activation, results in recruitment of neutrophils to the corneal stroma and TLR4-dependent fungal killing.

【 授权许可】

CC BY