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Hsin Chien, Emily Blalock, Christine Alston, Richard Dix; Cell death pathway inhibitors do not significantly reduce the frequency or severity of murine cytomegalovirus (MCMV) retinitis in mice with retrovirus-induced Immunosuppression (MAIDS). Invest. Ophthalmol. Vis. Sci. 2013;54(15):131. doi: https://doi.org/.
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The relative roles of apoptosis, pyroptosis, and necroptosis during AIDS-related HCMV retinitis development remain unclear. We recently provided evidence for simultaneous operation of all three cell death pathways during experimental MAIDS-related MCMV retinitis (J Virol 86:10961, 2012). We therefore hypothesized that selective inhibition of individual cell death pathway(s) will significantly reduce the frequency and/or severity of MCMV retinal disease during MAIDS. This hypothesis was tested using a pan-caspase inhibitor (Z-VAD-FMK), a caspase-1 inhibitor (Z-YVAD-FMK), or necrostatin-1 (nec-1) to abolish apoptosis/pyroptosis, pyroptosis, or necroptosis, respectively.
Groups of C57BL/6 mice with MAIDS were injected subretinally with MCMV and systemically treated daily with Z-VAD-FMK, Z-YVAD-FMK, nec-1, or vehicle (control). Eyes from all groups were collected 10 days later, analyzed histopathologically, and scored for frequency and severity of retinitis. Parallel MCMV-infected eye sections were subjected to TUNEL assay.
MCMV-infected eyes from MAIDS mice treated with vehicle showed a high frequency (100%) and severity (3.67) of retinitis. Surprisingly, MCMV-infected eyes from all MAIDS mice treated with each inhibitor continued to show a dampened yet high and equivalent retinitis frequency (80%). Differences in retinitis severity, however, were observed among drug-treated groups. MAIDS mice treated with the necroptosis inhibitor showed a severity score of 2.67, but MAIDS mice treated with the apoptosis/pyroptosis or pyroptosis inhibitors showed a severity score of 2.33. When compared with control MAIDS mice by TUNEL staining, MCMV-infected eyes of MAIDS mice treated with each inhibitor showed reduced TUNEL staining, the least observed following treatment with the apoptosis/pyroptosis or pyroptosis inhibitors. Decreased TUNEL staining was observed in the retinal pigment epithelium.
Inhibitors of apoptosis/pyroptosis, pyroptosis, or necroptosis dampened retinitis frequency and severity during MAIDS, but failed to reduce significantly overall retinal disease development as hypothesized. It is possible that loss of one cell death pathway is replaced by others to yield consistently high levels of retinal tissue damage during MAIDS-related MCMV retinitis.
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