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Kai Hu, Deshea Harris, Takefumi Yamaguchi, Homayon Ghiasi, Ulrich von Andrian, Pedram Hamrah, ; The role of corneal Plasmacytoid Dendritic Cells in acute herpes simplex virus infection. Invest. Ophthalmol. Vis. Sci. 2013;54(15):2158.
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We have recently demonstrated the presence of residential plasmacytoid dendritic cells (pDCs) in the murine cornea. In order to determine the function of corneal pDC, our purpose was to investigate the role of pDCs in acute herpes simplex virus (HSV)-1 keratitis.
Murine corneas were inoculated with HSV-1 after scarification. Corneal pDCs were depleted with subconjunctival (s.c.) injection of diphtheria toxin (DT) into BDCA-2-DTR or wild type (WT, C57BL/6) controls (sham-depleted). Clinical opacity scores were graded, and corneas were collected for immunofluorescence staining for pDC and analysis for HSV-1 virus titers. Corneas were analyzed for IFN-a mRNA and protein levels. CPG-ODN-1862, a Toll Like Receptor 9 (TLR9) agonist, was applied to the cornea after mechanical debridement in the presence and absence of pDC to test if increased IFN-a by pDC is TLR9-mediated.
As early as day 1 post inoculation (p.i.) with HSV-1, pDC density of central and peripheral corneas were significantly increased as compared to sham infection (p<0.05), and continuously increased on days 2, 4, 6 p.i. pDC were successfully depleted (>90%) by s.c. DT injections every 3 days. The corneal opacity scores and corneal virus titers in pDC-depleted mice [pDC(-)] were significantly increased compared to sham-depleted corneas (p<0.05) on days 1, 3, 5, 7 p.i. Corneal IFN-a mRNA and protein levels significantly increased on day 1, 3, 5, p.i. (p<0.05), with a peak 18-fold (mRNA) and 12-fold (protein) expression on day 3 p.i. compared with sham infection (p<0.01). However, pDC-depletion resulted in significant decrease (p<0.05) in both mRNA and protein levels of IFN-a. CPG-ODN-1862 application resulted in 5-fold (mRNA) (p<0.01) and 4-fold (protein) (p<0.01) increase in corneal IFN-a levels vs. CPG-ODN control, which was nearly abolished with depletion of pDC.
Corneal pDCs are the main producers of corneal IFN-a in HSV keratitis in a TLR9-mediated fashion and thus participate in the first-line defense against viral pathogens.
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