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SS Atherton, H Xin; Role of Macrophages and Nitric Oxide (NO) During Murine Cytomegalovirus (MCMV) Retinitis . Invest. Ophthalmol. Vis. Sci. 2002;43(13):1857.
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Purpose: Although macrophages are important in control of nonocular CMV infections, the role of macrophages during ocular infection is not known. The aims of this study were to determine the role of macrophages during ocular MCMV infection and whether nitric oxide (NO) plays a role in macrophage activity in the eye. Methods: Adult female BALB/c mice were depleted of macrophages by i.v. injection of liposomes containing clodronate on day -2, +2, and +6 or mock depleted by i.v. injection of liposomes containing PBS. On day 0, mice were inoculated with 5 × 103 PFU of MCMV (Smith strain) via the supraciliary route; mice were sacrificed on days 3, 5, 7, and 10 p.i. Spleens were removed and the extent of macrophage depletion determined by flow cytometry of FITC-F480 positive spleen cells. Frozen sections of MCMV-injected eyes were stained with biotinylated-F480 antibody to determine the extent of ocular macrophage depletion. The presence and extent of retinitis were determined by microscopic examination of sections stained with antibody specific for MCMV early antigen (EA). The titer of virus in MCMV injected eyes was determined by plaque assay. The role of NO was studied using wild-type control mice (C57BL/6) and iNOS-/- mice inoculated with 5 × 103 PFU of MCMV via the supraciliary route. Mice were sacrificed on days 7 and 10 p.i., and sections of MCMV-injected eyes were stained with FITC-MCMV EA antibody. Results: At all time points following i.v. injections of clodronate-containing liposomes, the number of F480+ macrophages was significantly reduced in the spleen and eye compared with control mice treated with PBS-containing liposomes. In macrophage-depleted mice, MCMV EA positive retinal cells and retinitis were observed beginning on day 5 p.i.; plaque assay confirmed replication of MCMV in MCMV infected eyes. Virus replication and retinitis were not observed in mock depleted mice. MCMV replication was also observed in the retinas of iNOS-/- mice whereas no virus replication was observed in the retinas of control mice. Conclusions: In the absence of other immunologic manipulation, depletion of macrophages alone allowed MCMV to spread to and replicate in the retina following supraciliary inoculation. Blocking production of NO from iNOS results in the same pattern of retinal infection as depletion of macrophages. Together, these results suggest that (a) macrophages play an important role in protecting the eye during MCMV infection and (b) antiviral activity of NO may be one mechanism by which macrophages modulate cytomegalovirus ocular infection.
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