Reduced frequency of murine cytomegalovirus retinitis in C57BL/6 mice correlates with low levels of suppressor of cytokine signaling (SOCS)1 and SOCS3 expression within the eye during corticosteroid-induced immunosuppression

Abstract

AIDS-related human cytomegalovirus retinitis remains a leading cause of blindness worldwide. We compared two C57BL/6 mouse models of experimental murine cytomegalovirus (MCMV) retinitis for intraocular expression of suppressors of cytokine signaling (SOCS)1 and SOCS3, host proteins that are inducible negative feedback regulators of cytokine signaling. These mouse models differed in method of immune suppression, one by retrovirus-induced immune suppression (MAIDS) and the other by corticosteroid-induced immune suppression. Following subretinal injection of MCMV to induce retinitis, intraocular SOCS1 and SOCS3 were only mildly stimulated, and often without significance, within MCMV-infected eyes during the progression of MCMV retinitis in corticosteroid-immunosuppressed mice, contrary to MCMV-infected eyes of mice with MAIDS that showed significant high stimulation of SOCS1 and SOCS3 expression in agreement with previous findings. Frequency and severity of retinitis as well as amounts of intraocular infectious MCMV in corticosteroid-immunosuppressed mice were also unexpectedly lower than values previously reported for MAIDS animals during MCMV retinitis. These data reveal a major difference between two mouse models of experimental MCMV retinitis and suggest a possible link between the amplitude of SOCS1 and SOCS3 stimulation and severity of disease in these models.

Keywords: AIDS-related cytomegalovirus retinitis; Corticosteroids; MAIDS; Murine cytomegalovirus; SOCS1; SOCS3; Suppressors of cytokine signaling (SOCS).

Figure 1. SOCS1 and SOCS3 expression is different in two different models of experimental MCMV retinitis

Groups of adult C57BL/6 mice with MAIDS of 10 weeks’ duration (A, B) and groups of adult C57BL/6 mice immune suppressed by corticosteroid treatment (C–F) were subretinally injected with 10⁴ PFU of MCMV (left eyes) or DMEM (right eyes) as described in Materials and Methods. Whole eyes were harvested at indicated times following subretinal MCMV injection and assessed by real-time RT-PCR assay using the comparative 2^−ΔΔCt method for quantification of SOCS1 mRNA expression within MCMV-infected eyes of MAIDS mice (A), SOCS3 mRNA expression within MCMV-infected eyes of MAIDS mice (B), SOCS1 mRNA expression with MCMV-infected eyes of corticosteroid-immunosuppressed mice (C), and SOCS3 mRNA expression of MCMV-infected eyes of corticosteroid-immunosuppressied mice (D). Ocular SOCS1 protein (E) and SOCS3 protein (F) were quantified at day 10 by ELISA from mice with corticosteroid-induced immunosuppression. Means ±SD of n = 5–8 mice per group are shown. * p<0.05 and ** p<0.01 for MCMV-infected eyes compared with media-injected controls.