Multiple Autonomous Cell Death Suppression Strategies Ensure Cytomegalovirus Fitness.
Viruses
; 13(9)2021 08 27.
Article
em En
| MEDLINE
| ID: mdl-34578288
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.
Palavras-chave
BCL2 family; DNA virus; HCMV; IFN; M36; M38.5; M41.1; M45; MCMV; RIPK1; RIPK3; TNF; UL36; apoptosis; cell death; cmvPCD; cytomegalovirus; extrinsic apoptosis; herpesvirus; inflammation; intrinsic apoptosis; macrophages; mitochondria; myeloid cells; necroptosis; pyroptosis; replication; serine protease; vIBO Caspase-8; vICA; vIRA; vMIA
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
/
Morte Celular
/
Muromegalovirus
Limite:
Animals
Idioma:
En
Revista:
Viruses
Ano de publicação:
2021
Tipo de documento:
Article