Transcriptional analysis of immune response genes during pathogenesis of cytomegalovirus retinitis in mice with murine acquired immunodeficiency syndrome

• Type of Material: Article
• Authors: Jessica J. Carter, Georgia State University; Jesse M. Gardner, Georgia State University; Brent P. Poling, Georgia State University; Madeline M. Welch, Georgia State University; Judee Grace E. Nemeno, Georgia State University; John E. Houghton, Georgia State University; Richard Dix, Emory University
• Language: English
• Date: 2020-11-06
• Publisher: Public Library of Science (PLoS)
• Publication Version: Final Published Version
• Copyright Statement: © 2020 Carter et al
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.ppat.1009032
• Title of Journal or Parent Work: PLoS Pathogens
• Volume: 16
• Issue: 11
• Grant/Funding Information: This study was funded by NIH NEI RO1 EY024630 (RDD), NIH NEI P30 EY006360 (RDD), and NIH NEI T32 EY007092 (JJC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
• Keywords: AIDS-related HCMV; murine cytomegalovirus (MCMV); retinitis; immunosuppression; retrovirus-induced immunodeficiency; herpesvirus; Human cytomegalovirus (HCMV)
• Research Categories: Health Sciences, Immunology; Health Sciences, Public Health; Biology, Virology

Abstract

Human cytomegalovirus (HCMV) is an opportunistic human herpesvirus that causes a sight-threatening retinitis in immunosuppressed patients, especially those with AIDS. Using an established model of experimental murine cytomegalovirus (MCMV) retinitis in mice with retrovirus-induced immunodeficiency (MAIDS), we have been attempting to define with greater clarity the immunologic mechanisms that contribute to the progression of AIDS-related HCMV retinitis in the unique immunosuppressive setting of HIV infection. Toward this end, we provide herein a comprehensive assessment of immune response gene expression during the onset and development of MAIDS-related MCMV retinitis employing NanoString nCounter. In so doing, we analyzed and compared the intraocular expressions of 561 immune response genes within MCMV-infected eyes of groups of healthy mice, MCMV-infected mice with MAIDS of 4 weeks’ (MAIDS-4) duration, and MCMV-infected eyes of mice with MAIDS of 10 weeks’ (MAIDS-10) duration. These animal groups show a progression of retinal disease from absolute resistance to retinitis development in healthy mice to the development of classic full-thickness retinal necrosis in MAIDS-10 mice but through an intermediate stage of retinal disease development in MAIDS-4 mice. Our findings showed that increased susceptibility to MCMV retinitis during the progression of MAIDS is associated with robust upregulation or downregulation of a surprisingly large number of immune response genes that operate within several immune response pathways often unique to each animal group. Analysis of 14 additional immune response genes associated with programmed cell death pathways suggested involvement of necroptosis and pyroptosis during MAIDS-related MCMV retinitis pathogenesis. Use of the NanoString nCounter technology provided new and unexpected information on the immunopathogenesis of retinitis within MCMV-infected eyes of mice with retrovirus-induced immunosuppression. Our findings may provide new insights into the immunologic events that operate during the pathogenesis of AIDS-related HCMV retinitis.