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H. Chien, E. L. Blalock, C. L. Meier, R. D. Dix; Experimental Cytomegalovirus Retinal Necrosis in TNF- Knockout Mice With Retrovirus-Induced Immunosuppression. Invest. Ophthalmol. Vis. Sci. 2010;51(13):1177.
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We have reported previously that peak levels of TNF-α mRNA precedes the appearance of retinal necrosis in murine cytomegalovirus (MCMV)-infected eyes of mice with retrovirus-induced immunosuppression (MAIDS) suggesting that TNF-α contributes to retinal tissue destruction during MAIDS-related MCMV retinitis, probably through induction of apoptosis. If true, MCMV-infected eyes of MAIDS mice lacking TNF-α will show marked reduction of apoptosis-related caspase mRNAs concomitant with reduced retinal disease when compared with wildtype mice with MAIDS.
To begin testing this hypothesis, groups of C57BL/6 mice and TNFKO mice with MAIDS of 10-weeks duration were injected subretinally with MCMV or maintenance medium. At 10 days postinfection, whole eyes were collected from all animals and analyzed by real time RT-PCR assay for quantification of TNF-α, TNFR1, TNFR2, caspase 3, and caspase 8 mRNAs.
MCMV-infected eyes of wildtype MAIDS mice susceptible to retinal necrosis showed a 30-fold increase in TNF-α mRNA levels when compared with mock-injected eyes. A lack of detectable TNF-α mRNA in MCMV-infected eyes of TNFKO MAIDS mice was accompanied by a sharp decline in TNFR1 mRNA levels when compared with those of wildtype MAIDS mice, although caspase 3 and caspase 8 mRNA levels were dampened but not severely decreased as expected. Levels of TNFR2 mRNA were nearly equivalent in MCMV-infected eyes of TNFKO MAIDS mice and wildtype MAIDS mice.
Surprisingly, depletion of TNF-α during MAIDS resulted in a dampened yet continued high production of apoptosis-related caspase 3 and caspase 8 mRNAs within MCMV-infected eyes. While TNF-α no doubt plays a prominent role in apoptosis-induced retinal disease during MAIDS-related MCMV retinitis, our findings suggest that a pro-apoptotic mediator other than TNF-α may also contribute significantly to apoptotic events associated with MCMV retinal disease during MAIDS. We predict that histopathologic analysis of MCMV-infected eyes from TNFKO MAIDS mice will show reduced yet significant retinal necrosis when compared with high frequency and severity of retinal necrosis in MCMV-infected eyes from wildtype MAIDS mice.
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