Multiple Autonomous Cell Death Suppression Strategies Ensure Cytomegalovirus Fitness.

Pratyusha Mandal,Edward S Mocarski,Christopher P Dillon,Anita Louise Mccormick,Emad S Alnemri,Heather S Koehler,Liliana Hernandez,Douglas R Green,Linda Roback,Lynsey N Nagrani

doi:10.3390/v13091707

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 mitochondrial 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 enhances 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.

Highlights

In the arms race between eukaryotic hosts and pathogens, programmed cell death (PCD) mechanisms evolved as a network of pathways primarily intended to sustain health by resisting infection [1,2,3,4,5]
We showed that MCMV faces receptor interacting protein (RIP) kinase (RIPK)3-dependent necroptosis within ~6 to 9 h, TNFR1dependent CASP8 activation within ~12 h, and mitochondrial cell death within ~24 h of infection
MCMV was shed in saliva mediates horizontal transmission [88], so viral load in these glands may be considered an indicator of viral fitness

Summary

Introduction

In the arms race between eukaryotic hosts and pathogens, programmed cell death (PCD) mechanisms evolved as a network of pathways primarily intended to sustain health by resisting infection [1,2,3,4,5]. Cytomegalovirus (CMV) has evolved to be a ubiquitous, highly successful mammalian pathogen by employing an array of conserved immunomodulatory strategies that subvert anti-viral defenses, through the effective suppression of both extrinsic and intrinsic PCD pathways [10,11,12,13,14,15,16,17,18,19] These suppression strategies sustain human (H) and murine (M) CMV replication in cells and, most importantly, ensure fitness in vivo [10,12,13,14,15,16,17,18]

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Conclusion