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Nan Gao, Ashok Kumar, Hui Guo, Fushin X. Yu; Topical Flagellin-mediated Innate Defense Against Fungal Keratitis. Invest. Ophthalmol. Vis. Sci. 2011;52(14):5816.
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This study was to investigate whether flagellin, the ligand of Toll-like receptor-5 (TLR5), induced innate defense is sufficient to protect injured corneas from fungal infection.
Scarified corneas of adult B6, TLR5, Camp knockout, or polymorphonuclear leukocyte (PMN) depleted mice were pretreated with Pseudomonas flagellin and then inoculated with C. albicans. The corneas were compared for disease progression, cytokine and CRAMP expression, and PMN infiltration before and after C. albicans infection. Disease progress was recorded by digital photography and clinical scoring, cytokine levels were determined by ELISA, CRAMP expression was assessed by Western blotting, and PMN infiltration was measured by MPO determination. Protection against Aspergillus fumigates was also tested in B6 mice.
Topical application of flagellin 6 or 24 h prior to Candida inoculation significantly improved disease outcome and shortened the time required for recovery of corneal transparency in a TLR5-dependent manner. Similar protective effects were observed B6 mouse corneas inoculated with for with 105 A. fumigates hyphae .Flagellin pretreatment resulted in dampened expression of IL-1β and MIP-2, reduced infiltration of PMN, significantly decreased fungal burdens as early as 6 h, and totally eliminated invading pathogens at 3 dpi. Both PMN depletion and Camp ablation resulted in great increases in fungal load without systemic fungal dissemination. Flagellin failed to induce C. albicans clearance, resulting in corneal perforation in both neutropenic and Camp-/- mice with or without flagellin pretreatment.
Flagellin induces a strong innate immune response to microbial infection in a non-pathogen dependent manner. Thus, topical flagellin or its mimetic might become a new prophylactic agent for preventing contact lens or trauma/injury-associated microbial keratitis.
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