Evidence For Multiple Cell Death Pathways during Development of Experimental Cytomegalovirus Retinitis in Mice with Retrovirus-Induced Immunosuppression: Apoptosis, Necroptosis, and Pyroptosis

• Type of Material: Article
• Authors: Hsin Chien, Georgia State University; Richard Dix, Emory University
• Language: English
• Date: 2012-10-01
• Publisher: American Society for Microbiology
• Publication Version: Final Published Version
• Copyright Statement: © 2012, American Society for Microbiology.
• Final Published Version (URL): http://dx.doi.org/10.1128/JVI.01275-12
• Title of Journal or Parent Work: Journal of Virology
• ISSN: 0022-538X
• Volume: 86
• Issue: 20
• Start Page: 10961
• End Page: 10978
• Grant/Funding Information: This work was supported in part by NIH/NEI grant EY010568, NIH/NEI core grant P30EY006360, and Fight for Sight, Inc.
• Keywords: Life Sciences & Biomedicine; IMMUNE-RESPONSES; TUMOR-NECROSIS-FACTOR; FACTOR-ALPHA; VIRAL LOAD; FACTOR RECEPTOR; MURINE CYTOMEGALOVIRUS; PROGRAMMED NECROSIS; Science & Technology; DAI DLM-1/ZBP1; DNA FRAGMENTATION; RIBONUCLEOTIDE REDUCTASE HOMOLOG; Virology; VIROLOGY
• Research Categories: Health Sciences, Immunology; Health Sciences, Opthamology

Abstract

AIDS-related human cytomegalovirus (HCMV) retinitis remains a major ophthalmologic problem worldwide. Although this sight-threatening disease is well characterized clinically, many pathogenic issues remain unresolved, among them a basic understanding of the relative roles of cell death pathways during development of retinal tissue destruction. Using an established model of experimental murine cytomegalovirus (MCMV) retinitis in mice with retrovirus-induced immunosuppression (MAIDS), we initially investigated MCMV-infected eyes for evidence of apoptosis-associated molecules in mice with MAIDS of 4 weeks' (MAIDS-4) and 10 weeks' (MAIDS-10) duration, which were resistant and susceptible to retinal disease, respectively, but which harbored equivalent amounts of infectious MCMV. Whereas MCMV-infected eyes of MAIDS-4 mice showed little evidence of apoptosis-associated molecules, MCMV-infected eyes of MAIDS-10 mice showed significant amounts of tumor necrosis factor alpha (TNF-(α), TNF receptors 1 and 2, active caspase 8, active caspase 3, TNF-related apoptosis-inducing ligand (TRAIL), TRAIL-R(DR5), Fas, and Fas ligand mRNAs and/or proteins, all detected at peak amounts prior to development of most severe retinal disease. Immunohistochemical staining showed macrophages, granulocytes (neutrophils), Müller cells, and microglial cells as TNF-α sources. Remarkably, quantification of apoptosis by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) assay suggested that apoptosis contributed minimally to retinal disease in MCMV-infected eyes of MAIDS-10 mice. Subsequent studies demonstrated that MCMV-infected eyes of MAIDS-10 mice, but not MAIDS-4 mice, showed evidence of significant increases in molecules associated with two additional cell death pathways, necroptosis (receptorinteracting protein 1 [RIP1] and RIP3 mRNAs) and pyroptosis (caspase 1, interleukin 1(β [IL-1β] , and IL-18 mRNAs). We conclude that apoptosis, necroptosis, and pyroptosis participate simultaneously during MAIDS-related MCMV retinitis, and all may play a role during AIDS-related HCMV retinitis.