RGD Reference Report - Distinct roles for Dectin-1 and TLR4 in the pathogenesis of Aspergillus fumigatus keratitis. - Rat Genome Database

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

Authors: Leal SM, JR  Cowden, S  Hsia, YC  Ghannoum, MA  Momany, M  Pearlman, E 
Citation: Leal SM Jr, etal., PLoS Pathog. 2010 Jul 1;6:e1000976. doi: 10.1371/journal.ppat.1000976.
RGD ID: 7794847
Pubmed: (View Article at PubMed) PMID:20617171
DOI: Full-text: DOI:10.1371/journal.ppat.1000976

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.

Disease Annotations    
Fungal Keratitis  (IMP,ISO)

Objects Annotated

Genes (Rattus norvegicus)
Tlr4  (toll-like receptor 4)

Genes (Mus musculus)
Tlr4  (toll-like receptor 4)

Genes (Homo sapiens)
TLR4  (toll like receptor 4)

Additional Information