Programmed cell death and cytomegalovirus retinitis pathogenesis

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Program Director/Principal Investigator (Last, First, Middle): Dix, Richard D Project Summary Programmed cell death (PCD) operates during innate immunity to eliminate virus-infected cells and regulate infection-associated inflammation during virus invasion. Little information is available regarding the precise contributions of PCD toward the pathogenesis of retinal diseases of virus origin, especially those caused by herpesviruses including AIDS-related human cytomegalovirus (HCMV) retinitis. A critical barrier to progress in advancing our ability to diagnose, prevent, and/or treat herpesvirus retinal diseases has been a lack of information on the possible contributions of different forms of PCD toward onset and development of these virus-induced retinal diseases including AIDS-related HCMV retinitis. Our goal is to address this knowledge deficit and the critical barrier to progress by obtaining new information needed to define the relative individual and collective roles of apoptosis, necroptosis, and pyroptosis during onset and development of this sight- threatening eye disease using an established mouse model of murine cytomegalovirus (MCMV) retinitis in mice with retrovirus-induced immunosuppression (MAIDS). Our central hypothesis is that apoptosis, necroptosis, and pyroptosis conspire via different mechanisms to contribute to the severe retinal tissue destruction during MAIDS-related MCMV retinitis pathogenesis. Our objectives are to use the MAIDS model of MCMV retinitis to (1) obtain the information needed to understand the precise contributions and begin to understand the mechanisms by which these PCD pathways contribute to retinal tissue destruction and loss of function, (2) explore the mechanisms by which these PCD pathways stimulate inflammation within retinal tissues during retinal disease onset and development, and (3) establish that PCD inhibitors represent a new therapeutic approach for management of cytomegalovirus retinal disease. These objectives will be met through successful completion of three Specific Aims: (1) test the hypothesis that multiple PCD pathways contribute to retinal tissue destruction during MAIDS-related MCMV retinitis pathogenesis, (2) test the hypothesis that PCD- initiated inflammation plays a critical role in development of retinal tissue destruction during MAIDS-related MCMV retinitis pathogenesis, and (3) test the hypothesis that PCD inhibitors will alter the onset and progression of MAIDS-related MCMV retinitis. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page