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Hsin Chien, Emily L. Blalock, Courtney L. Meier-Jewett, Christine I. Alston, Richard D. Dix; Experimental Cytomegalovirus Retinitis in TNF-α Ligand or TNF-α Receptor Knockout Mice with Retrovirus-induced Immunosuppression. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2969.
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Previous work has suggested that increased levels of TNF-α within murine cytomegalovirus (MCMV)-infected eyes contribute to retinitis in mice with retrovirus-induced immunosuppression (MAIDS). To define with greater precision the role of TNF-α in development of MAIDS-related MCMV retinitis, we performed additional studies using MAIDS mice deficient in either TNF-α ligand (TNFKO mice) or TNF-α receptors (TNFR1KO and TNFR2KO mice).
Groups of wildtype C57BL/6 mice, TNFKO mice, TNFR1KO, and TNFR2KO mice, all with MAIDS of 10-weeks duration, were inoculated subretinally with MCMV or mock-injected. At 3, 6, and 10 days postinfection, MCMV-infected and mock-injected whole eyes were collected from all animals and subjected to real time RT-PCR for quantification of TNF-α, TNFR1, TNFR2, caspase 3, and caspase 8 mRNAs. Whole eyes from parallel animal groups were analyzed histopathologically for frequency of retinitis, quantification of infectious virus, and quantification of apoptosis by TUNEL assay.
Whereas 90% of MCMV-infected eyes of wildtype mice with MAIDS exhibited retinitis at 10 days postinfection, 10% of MCMV-infected eyes of TNFKO mice with MAIDS showed retinitis. Nonetheless, MCMV-infected eyes of wildtype MAIDS mice with retinitis and TNFKO MAIDS mice without retinitis harbored equivalent high amounts of intraocular infectious virus. Depletion of TNF-α during MAIDS resulted in a dampened yet continued production of apoptosis-related caspase 3 and caspase 8 mRNAs. Peak numbers of apoptotic cells in retinal tissues of MCMV-infected eyes of wildtype mice with MAIDS were found at 6 days postinfection and preceded appearance of retinal necrosis at 10 days postinfection. Apoptotic cells in retinal tissues of MCMV-infected eyes of wildtype mice with MAIDS at 10 days postinfection accounted for a small percentage (~8%) of retinal cells, and only ~2% of retinal cells were found to exhibit apoptosis in MCMV-infected eyes of TNFKO, TNFR1, and TNFR2 mice with MAIDS.
Although TNF-α contributes to MCMV retinitis during MAIDS, apoptosis may play only a minimal role in its development.
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