Virus-induced senescence is a driver and therapeutic target in COVID-19.
Nature
; 599(7884): 283-289, 2021 11.
Article
in English
| MEDLINE | ID: covidwho-1404888
ABSTRACT
Derailed cytokine and immune cell networks account for the organ damage and the clinical severity of COVID-19 (refs. 1-4). Here we show that SARS-CoV-2, like other viruses, evokes cellular senescence as a primary stress response in infected cells. Virus-induced senescence (VIS) is indistinguishable from other forms of cellular senescence and is accompanied by a senescence-associated secretory phenotype (SASP), which comprises pro-inflammatory cytokines, extracellular-matrix-active factors and pro-coagulatory mediators5-7. Patients with COVID-19 displayed markers of senescence in their airway mucosa in situ and increased serum levels of SASP factors. In vitro assays demonstrated macrophage activation with SASP-reminiscent secretion, complement lysis and SASP-amplifying secondary senescence of endothelial cells, which mirrored hallmark features of COVID-19 such as macrophage and neutrophil infiltration, endothelial damage and widespread thrombosis in affected lung tissue1,8,9. Moreover, supernatant from VIS cells, including SARS-CoV-2-induced senescence, induced neutrophil extracellular trap formation and activation of platelets and the clotting cascade. Senolytics such as navitoclax and a combination of dasatinib plus quercetin selectively eliminated VIS cells, mitigated COVID-19-reminiscent lung disease and reduced inflammation in SARS-CoV-2-infected hamsters and mice. Our findings mark VIS as a pathogenic trigger of COVID-19-related cytokine escalation and organ damage, and suggest that senolytic targeting of virus-infected cells is a treatment option against SARS-CoV-2 and perhaps other viral infections.
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Cellular Senescence
/
Molecular Targeted Therapy
/
SARS-CoV-2
/
COVID-19
/
COVID-19 Drug Treatment
Type of study:
Prognostic study
Topics:
Long Covid
Limits:
Animals
/
Female
/
Humans
/
Male
Language:
English
Journal:
Nature
Year:
2021
Document Type:
Article
Affiliation country:
S41586-021-03995-1
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