Emily L. Blalock

Murine cytomegalovirus downregulates interleukin-17 in mice with retrovirus-induced immunosuppression that are susceptible to experimental cytomegalovirus retinitis.

Interleukin-17 (IL-17), a pro-inflammatory cytokine produced by CD4+ Th17 cells, has been associated with the pathogenesis of several autoimmune diseases including uveitis. The fate of IL-17 during HIV/AIDS, however, remains unclear, and a possible role for IL-17 in the pathogenesis of AIDS-related diseases has not been investigated. Toward these ends, we performed studies using a well-established animal model of experimental murine cytomegalovirus (MCMV) retinitis that develops in C57/BL6 mice with retrovirus-induced immunosuppression (MAIDS). After establishing baseline levels for IL-17 production in whole splenic cells of healthy mice, we observed a significant increase in IL-17 mRNA levels in whole splenic cells of mice with MAIDS of 4-weeks (MAIDS-4), 8-weeks (MAIDS-8), and 10-weeks (MAIDS-10) duration. In contrast, enriched populations of splenic CD4+ T cells, splenic macrophages, and splenic neutrophils exhibited a reproducible decrease in levels of IL-17 mRNA during MAIDS progression. To explore a possible role for IL-17 during the pathogenesis of MAIDS-related MCMV retinitis, we first demonstrated constitutive IL-17 expression in retinal photoreceptor cells of uninfected eyes of healthy mice. Subsequent studies, however, revealed a significant decrease in intraocular levels of IL-17 mRNA and protein in MCMV-infected eyes of MAIDS-10 mice during retinitis development. That MCMV infection might cause a remarkable downregulation of IL-17 production was supported further by the finding that systemic MCMV infection of healthy, MAIDS-4, or MAIDS-10 mice also significantly decreased IL-17 mRNA production by splenic CD4+ T cells. Based on additional studies using IL-10 -/- mice infected systemically with MCMV and IL-10 -/- mice with MAIDS infected intraocularly with MCMV, we propose that MCMV infection downregulates IL-17 production via stimulation of suppressor of cytokine signaling (SOCS)-3 and interleukin-10.

Systemic reduction of interleukin-4 or interleukin-10 fails to reduce the frequency or severity of experimental cytomegalovirus retinitis in mice with retrovirus-induced immunosuppression.

Interleukin-4 (IL-4) and interleukin-10 (IL-10) are key cytokines whose increased production during systemic HIV infection has been associated with decreased cellular immunity during AIDS. We examined whether HIV-induced stimulation of IL-4 or IL-10 production leads to increased susceptibility to AIDS-related human cytomegalovirus retinitis. It was confirmed that there were increased amounts of IL-4 and IL-10 mRNA levels in mice with MAIDS of 10 weeks duration when most susceptible to MCMV retinitis. Surprisingly, however, MCMV-infected eyes of IL-4 –/– and IL-10 –/– mice with MAIDS of 8 weeks duration exhibited retinitis and infectious virus equivalent to that observed in MCMV-infected eyes of wild-type mice with MAIDS. We conclude that neither IL-4 nor IL-10 alone play a role in increased susceptibility to MAIDS-related MCMV retinitis, but may work collectively with other retrovirus-induced immunosuppressive factors to allow for retinal disease.