Human cytomegalovirus (HCMV) is a species-specific β-herpesvirus that establishes a lifelong latent infection in ~80% of the world’s population and can cause severe opportunistic diseases in immunosuppressed patients including those with AIDS. Of these, AIDS-related HCMV retinitis is a significant ophthalmological problem worldwide. Although the clinical features of AIDS-related HCMV retinitis are well established, the virologic and immunologic events that take place during onset and development of this sight-threatening retinal disease remain poorly understood. Toward this end, an established animal model of murine cytomegalovirus (MCMV) retinitis in mice with retrovirus-induced immunodeficiency (MAIDS) that mimics AIDS-related HCMV retinitis was used in the present investigation to test the central hypothesis that pyroptosis, as a programmed cell death pathway of innate immunity, and associated inflammasomes contribute to the onset and development of full-thickness retinal necrosis during MAIDS-related MCMV retinitis. Our findings show (i) intraocular MCMV infection stimulates key pyroptosis-associated transcripts and proteins within the eyes of retinitis-susceptible MAIDS mice but not within the eyes of retinitis-resistant mice; (ii) a deficiency in key pyroptosis-associated molecules and inflammasomes in MAIDS mice results in an atypical histopathologic pattern of retinal disease within MCMV-infected eyes characterized by preservation of the neurosensory retina without full-thickness retinal necrosis but with proliferation of the retinal pigmented epithelium; (iii) MCMV-infected eyes of corticosteroid-immunosuppressed mice display stimulation of key pyroptosis-associated molecules and inflammasomes similar to that observed for MCMV-infected eyes of mice with MAIDS; (iv) MCMV infection of IC-21 macrophages and mouse embryo fibroblasts grown in culture stimulates key pyroptosis-associated transcripts in a cell-type specific manner; and (v) increased susceptibility to MCMV retinitis during the progression of MAIDS is associated with robust upregulation of a surprisingly large number of immune response genes that operate within several immune response pathways. Taken together, these results suggest that pyroptosis and associated inflammasomes play a significant role during the pathogenesis of full-thickness retinal necrosis within MCMV-infected eyes during MAIDS. These findings add new knowledge to our understanding of the contributions of programmed cell death pathways of innate immunity towards the pathogenesis of AIDS-related HCMV retinitis and may extend to other AIDS-related opportunistic virus infections.
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