Virus-induced senescence is driver and therapeutic target in COVID-19.

Lee, Soyoung; Yu, Yong; Trimpert, Jakob; Benthani, Fahad; Mairhofer, Mario; Richter-Pechanska, Paulina; Wyler, Emanuel; Belenki, Dimitri; Kaltenbrunner, Sabine; Pammer, Maria; Kausche, Lea; Firsching, Theresa C; Dietert, Kristina; Schotsaert, Michael; Martínez-Romero, Carles; Singh, Gagandeep; Kunz, Séverine; Niemeyer, Daniela; Ghanem, Riad; Salzer, Helmut J F; Paar, Christian; Mülleder, Michael; Uccellini, Melissa; Michaelis, Edward G; Khan, Amjad; Lau, Andrea; Schönlein, Martin; Habringer, Anna; Tomasits, Josef; Adler, Julia M; Kimeswenger, Susanne; Gruber, Achim D; Hoetzenecker, Wolfram; Steinkellner, Herta; Purfürst, Bettina; Motz, Reinhard; Di Pierro, Francesco; Lamprecht, Bernd; Osterrieder, Nikolaus; Landthaler, Markus; Drosten, Christian; García-Sastre, Adolfo; Langer, Rupert; Ralser, Markus; Eils, Roland; Reimann, Maurice; Fan, Dorothy N Y; Schmitt, Clemens A

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.