Date of Award

12-16-2020

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

First Advisor

Dr. Richard D. Dix

Second Advisor

Dr. Julia K. Hilliard

Third Advisor

Dr. Yuan Liu

Fourth Advisor

Dr. Homayon Ghiasi

Abstract

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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