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

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 J.F. SalzerChristian 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 N.Y. Fan, Clemens A. Schmitt

Research output: Contribution to journalArticlepeer-review

75 Scopus citations

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.

Original languageEnglish
Pages (from-to)283-289
Number of pages7
JournalNature
Volume599
Issue number7884
DOIs
StatePublished - 11 Nov 2021

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