Virus-induced senescence is a driver and therapeutic target in COVID-19
Authors list
Soyoung Lee Yong Yu Jakob Trimpert Fahad Benthani Mario Mairhofer Paulina Richter-Pechanska Emanuel Wyler Dimitri Belenki Sabine Kaltenbrunner Maria Pammer Lea Kausche Theresa C Firsching Kristina Dietert Michael Schotsaert Carles Martínez-Romero Gagandeep Singh Séverine Kunz Daniela Niemeyer Riad Ghanem Helmut JF Salzer Christian Paar Michael Mülleder Melissa Uccellini Edward G Michaelis Amjad Khan Andrea Lau Martin Schönlein Anna Habringer Josef Tomasits Julia M Adler Susanne Kimeswenger Achim D Gruber Wolfram Hoetzenecker Herta Steinkellner Bettina Purfürst Reinhard Motz Francesco Di Pierro Bernd Lamprecht Nikolaus Osterrieder Markus Landthaler Christian Drosten Adolfo García-Sastre Rupert Langer Markus Ralser Roland Eils Maurice Reimann Dorothy NY Fan Clemens A Schmitt Toggle all authors (48)
Abstract
Derailed cytokine and immune cell networks account for organ damage and clinical severity of COVID-191-4. 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 accompanied by a senescence-associated secretory phenotype (SASP), composed of pro-inflammatory cytokines, extracellular matrix-active factors and pro-coagulatory mediators5-7. COVID-19 patients displayed markers of senescence in their airway mucosa in situ and elevated serum levels of SASP factors. Mirroring COVID-19 hallmark features such as macrophage and neutrophil infiltration, endothelial damage and widespread thrombosis in affected lung tissue1,8,9, in vitro assays demonstrated macrophage activation with SASP-reminiscent secretion, complement lysis and SASP-amplifying secondary senescence of endothelial cells, neutrophil extracellular trap (NET) formation as well as activation of platelets and the clotting cascade in response to supernatant of VIS cells, including SARS-CoV-2-induced senescence. Senolytics such as Navitoclax and Dasatinib/Quercetin selectively eliminated VIS cells, mitigated COVID-19-reminiscent lung disease and reduced inflammation in SARS-CoV-2-driven hamster and mouse models. Our findings mark VIS as pathogenic trigger of COVID-19-related cytokine escalation and organ damage, and suggest senolytic targeting of virus-infected cells as a novel treatment option against SARS-CoV-2 and perhaps other viral infections.
Journal details
Journal Nature
Volume 599
Issue number 7884
Pages 283-289
Available online
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Publisher website (DOI) 10.1038/s41586-021-03995-1
Europe PubMed Central 34517409
Pubmed 34517409
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