The causative agent of the COVID-19 pandemic, the human pathogenic coronavirus SARS-CoV-2, causes upper respiratory infections and subsequently lung disease that may become further complicated by septic multiorgan failure and is associated with increased mortality 10, 11. 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.
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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. Moreover, supernatant from VIS cells, including SARS-CoV-2-induced senescence, induced neutrophil extracellular trap formation and activation of platelets and the clotting cascade.
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 1, 8, 9. Patients with COVID-19 displayed markers of senescence in their airway mucosa in situ and increased serum levels of SASP factors. 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 5, 6, 7. Here we show that SARS-CoV-2, like other viruses, evokes cellular senescence as a primary stress response in infected cells.
Nature volume 599, pages 283–289 ( 2021) Cite this articleĭerailed cytokine and immune cell networks account for the organ damage and the clinical severity of COVID-19 (refs.
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Virus-induced senescence is a driver and therapeutic target in COVID-19