Distinct roles for Dectin-1 and TLR4 in the pathogenesis of Aspergillus fumigatus keratitis.

Academic Article

Abstract

  • 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-1beta and CXCL1/KC, and for recruitment of neutrophils and mononuclear cells into the corneal stroma. We found that beta-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-1beta and CXCL1/KC production, resulting in diminished cellular infiltration and fungal clearance compared with control mice, especially during infection with clinical isolates expressing high beta-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 beta-glucan on A.fumigatus germinating conidia activates Dectin-1 on corneal macrophages to produce IL-1beta, and CXCL1, which together with IL-1R1/MyD88-dependent activation, results in recruitment of neutrophils to the corneal stroma and TLR4-dependent fungal killing.
  • Authors

    Published In

  • PLoS Pathogens  Journal
  • Keywords

  • Animals, Aspergillus fumigatus, Chemokine CXCL1, Corneal Stroma, Interleukin-1beta, Intracellular Signaling Peptides and Proteins, Keratitis, Lectins, C-Type, Macrophages, Membrane Proteins, Mice, Nerve Tissue Proteins, Protein-Tyrosine Kinases, Syk Kinase, Toll-Like Receptor 4, beta-Glucans
  • Digital Object Identifier (doi)

    Author List

  • Leal SM; Cowden S; Hsia Y-C; Ghannoum MA; Momany M; Pearlman E
  • Start Page

  • e1000976
  • Volume

  • 6