Multiple Autonomous Cell Death Suppression Strategies Ensure Cytomegalovirus Fitness

• Type of Material: Article
• Authors: Pratyusha Mandal, Emory University; Lynsey N Nagrani, Pharmaceutical Product Development; Liliana Hernandez, Emory University; Anita McCormick, Emory University; Christopher P Dillon, Pfizer Inc; Heather S Koehler, Emory University; Linda Roback, Emory University; Emad S Alnemri, Thomas Jefferson Univ; Douglas R Green, St. Jude Children’s Research Hospital; Edward Mocarski, Emory University
• Language: English
• Date: 2021-09-01
• Publisher: MDPI
• Publication Version: Final Published Version
• Copyright Statement: © 2021 by the authors.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3390/v13091707
• Title of Journal or Parent Work: VIRUSES-BASEL
• Volume: 13
• Issue: 9
• Grant/Funding Information: This research was funded by NIAID R01 AI030363 and AI020211 to ESM; R21 AI142507 to A.L.M. and E.S.M; Emory CF@tlanta Director’s Fund to PM, Halle Institute Global Grant 2020 to PM and E.S.M and NIAMS AR074564 to ESA.
• Keywords: BACTERIAL ARTIFICIAL CHROMOSOME; RIPK3; BCL-2; MCMV; pyroptosis; serine protease; extrinsic apoptosis; FAMILY-MEMBERS; 5; vIBO Caspase-8; NECROSIS; M45; apoptosis; CHEMOKINE HOMOLOG; UL36; cell death; ALPHA-INDUCED APOPTOSIS; herpesvirus; vMIA; IFN; M38; HCMV; vIRA; necroptosis; mitochondria; BCL2 family; macrophages; MYXOMA VIRUS; 1; intrinsic apoptosis; TNF; M41; RIPK1; Science & Technology; vICA; DNA virus; myeloid cells; inflammation; MITOCHONDRIA-LOCALIZED INHIBITOR; replication; cytomegalovirus; BAX; Life Sciences & Biomedicine; cmvPCD; Virology; M36; VIRAL INHIBITOR
• Research Categories: Health Sciences, Immunology; Chemistry, Biochemistry; Biology, Microbiology

Abstract

Programmed cell death pathways eliminate infected cells and regulate infection-associated inflammation during pathogen invasion. Cytomegaloviruses encode several distinct suppressors that block intrinsic apoptosis, extrinsic apoptosis, and necroptosis, pathways that impact pathogenesis of this ubiquitous herpesvirus. Here, we expanded the understanding of three cell autonomous suppression mechanisms on which murine cytomegalovirus relies: (i) M38.5-encoded viral mitochon-drial inhibitor of apoptosis (vMIA), a BAX suppressor that functions in concert with M41.1-encoded viral inhibitor of BAK oligomerization (vIBO), (ii) M36-encoded viral inhibitor of caspase-8 activation (vICA), and (iii) M45-encoded viral inhibitor of RIP/RHIM activation (vIRA). Following infection of bone marrow-derived macrophages, the virus initially deflected receptor-interacting protein kinase (RIPK)3-dependent necroptosis, the most potent of the three cell death pathways. This process remained independent of caspase-8, although suppression of this apoptotic protease en-hances necroptosis in most cell types. Second, the virus deflected TNF-mediated extrinsic apoptosis, a pathway dependent on autocrine TNF production by macrophages that proceeds independently of mitochondrial death machinery or RIPK3. Third, cytomegalovirus deflected BCL-2 family protein-dependent mitochondrial cell death through combined TNF-dependent and-independent signaling even in the absence of RIPK1, RIPK3, and caspase-8. Furthermore, each of these cell death pathways dictated a distinct pattern of cytokine and chemokine activation. Therefore, cytomegalovirus employs sequential, non-redundant suppression strategies to specifically modulate the timing and execution of necroptosis, extrinsic apoptosis, and intrinsic apoptosis within infected cells to orchestrate virus control and infection-dependent inflammation. Virus-encoded death suppressors together hold control over an intricate network that upends host defense and supports pathogenesis in the intact mammalian host.