Autophagy protects against retinal cell death in mouse model of cytomegalovirus retinitis

Background: Extensive death of uninfected bystander neuronal cells is an important component of the pathogenesis of cytomegalovirus retinitis (CMV). Our previous results have shown that there is a functional relationship between autophagy and apoptosis during MCMV infection of retinal pigment epithelium (RPE). The purpose of this study was to determine whether autophagy plays a significant role in the death of retinal cells during MCMV retinitis. Methods: The retinas of adult BALB/c mice were infected with MCMV via supraciliary injection. Rapamycin was injected to MCMV-infected BALB/c mice intraperitoneally. Immunohistochemistry and western blot were performed to observe the spread pattern of virus in retinas and the levels of targeted proteins. Plaque assay was performed to determine the virus titer in different groups. Nestin-cre; Atg5flox/flox mice were genotyped and infected with MCMV. Immunohistochemistry was performed to observe the type of virus-infected cells and apoptosis in retinas during MCMV retinitis. Results: In MCMV mouse model, MCMV infection in our nuclear layer (ONL) and inner nuclear layer (INL) in the retinas caused cleaved caspase 3 positive apoptosis, which is not co-localized with early antigen (EA) positive virus infected cells in rapamycin treated group. Rapamycin treatment increased the levels of LC3B-II by inhibiting mTOR and decreased the levels of cleaved caspase-3 during MCMV retinitis. However, virus propagation was not affected by rapamycin. In Nestin-cre; Atg5flox/flox mice, RPE and glial cells were the main targets of viral infection, and number of EA positive retinal cells and TUNEL positive retinal cells was significantly increased compared to Nestin-cre; Atg5flox/+ mice though there was no difference of virus propagation between Nestin-cre; Atg5flox/flox mice and Nestin-cre; Atg5flox/+ mice. Conclusions: Autophagy protects retinal cells from MCMV infection induced apoptosis through mTOR-mediated signaling pathway.