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Virus-induced senescence is a driver and therapeutic target in COVID-19.
- Source :
-
Nature [Nature] 2021 Nov; Vol. 599 (7884), pp. 283-289. Date of Electronic Publication: 2021 Sep 13. - Publication Year :
- 2021
-
Abstract
- Derailed cytokine and immune cell networks account for the organ damage and the clinical severity of COVID-19 (refs. <superscript>1-4</superscript> ). 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 mediators <superscript>5-7</superscript> . 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 tissue <superscript>1,8,9</superscript> . 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.<br /> (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)
- Subjects :
- Aniline Compounds pharmacology
Aniline Compounds therapeutic use
Animals
COVID-19 complications
Cell Line
Cricetinae
Dasatinib pharmacology
Dasatinib therapeutic use
Disease Models, Animal
Female
Humans
Male
Mice
Quercetin pharmacology
Quercetin therapeutic use
SARS-CoV-2 drug effects
Sulfonamides pharmacology
Sulfonamides therapeutic use
Thrombosis complications
Thrombosis immunology
Thrombosis metabolism
COVID-19 pathology
COVID-19 virology
Cellular Senescence drug effects
Molecular Targeted Therapy
SARS-CoV-2 pathogenicity
COVID-19 Drug Treatment
Subjects
Details
- Language :
- English
- ISSN :
- 1476-4687
- Volume :
- 599
- Issue :
- 7884
- Database :
- MEDLINE
- Journal :
- Nature
- Publication Type :
- Academic Journal
- Accession number :
- 34517409
- Full Text :
- https://doi.org/10.1038/s41586-021-03995-1