Date of Award
Doctor of Philosophy (PhD)
Richard D. Dix
Susanna F. Greer
Julia K. Hilliard
Human cytomegalovirus (HCMV) is a betaherpesvirus that infects up to 80% of the population worldwide, and establishes latency in monocytes and bone marrow cells. Reactivated HCMV can become an opportunistic pathogen in individuals who are immunocompromised, such as those with acquired immunodeficiency syndrome (AIDS). HCMV infection of AIDS patients causes a sight-threatening retinitis that leads to vision loss and blindness in up to 46% of this population without antiretroviral treatment. Because untreated HIV-infected individuals exhibit the loss of cell-mediated immunity and alterations in CD4+ T-helper (Th) cell cytokines, including elevation of interleukin-4 (IL-4), IL-10, and IL-17, we sought to test the hypothesis that these cytokines play key roles in governing the susceptibility to AIDS-related HCMV retinitis. This hypothesis was tested utilizing a clinically relevant mouse model of experimental murine cytomegalovirus (MCMV) retinitis that occurs in C57BL/6 mice immunosuppressed by mouse retroviruses (MAIDS). Studies revealed that MAIDS progression was associated with increased levels of IL-4 and IL-10, cytokines whose production has been associated with diminished CD8+ T-cell-mediated immunity during HIV infection. However, MCMV–infected eyes of retinitis-susceptible IL-4-/- or IL-10-/- MAIDS mice exhibited frequency and severity of retinitis and viral titers equivalent to MCMV-infected eyes of wild-type MAIDS animals. These studies indicated that neither IL-4 nor IL-10 alone play key roles in increased susceptibility to MCMV retinitis. In comparison, IL-17, an inflammatory cytokine associated with the ocular autoimmune disease uveitis, was systemically increased during the progression of MAIDS, but MCMV-infected eyes of retinitis-susceptible MAIDS mice exhibited a significant reduction in IL-17. These findings suggested that IL-17 plays no direct role in the pathogenesis of experimental MCMV retinitis. However, these results also suggested the remarkable possibility that MCMV downregulates IL-17 production, a hypothesis supported by the observation that systemic MCMV infection of healthy and MAIDS mice resulted in the downregulation of IL-17. Mechanistic studies revealed that knockdown of IL-10 resulted in a partial recovery IL-17 levels during MCMV infection. We conclude that MCMV-induced IL-17 downregulation occurs via the stimulation of IL-10 and the suppressor of cytokine signaling (SOCS)-3. Taken together, our results add new information to the immunobiology of HCMV and to our basic understanding of the pathogenesis of AIDS-related HCMV retinitis.
Blalock, Emily L., "Roles of TH2 and TH17 CD4+ T-Helper Cell Cytokines in the Pathogenesis of Experiemental Cytomegalovirus Retinitis" (2012). Biology Dissertations. Paper 122.
Available for download on Tuesday, November 26, 2013