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. 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 N. Y. Fan and Clemens A. Schmitt ()
Additional contact information
Soyoung Lee: Charité - Universitätsmedizin
Yong Yu: Johannes Kepler University
Jakob Trimpert: Freie Universität Berlin
Fahad Benthani: Johannes Kepler University
Mario Mairhofer: Johannes Kepler University
Paulina Richter-Pechanska: Charité - Universitätsmedizin
Emanuel Wyler: Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association
Dimitri Belenki: Charité - Universitätsmedizin
Sabine Kaltenbrunner: Johannes Kepler University
Maria Pammer: Johannes Kepler University
Lea Kausche: Charité - Universitätsmedizin
Theresa C. Firsching: Freie Universität Berlin
Kristina Dietert: Freie Universität Berlin
Michael Schotsaert: Icahn School of Medicine at Mount Sinai
Carles Martínez-Romero: Icahn School of Medicine at Mount Sinai
Gagandeep Singh: Icahn School of Medicine at Mount Sinai
Séverine Kunz: Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association
Daniela Niemeyer: Charité—Universitätsmedizin,
Riad Ghanem: Kepler University Hospital
Helmut J. F. Salzer: Kepler University Hospital
Christian Paar: Kepler University Hospital
Michael Mülleder: Charité - Universitätsmedizin
Melissa Uccellini: Icahn School of Medicine at Mount Sinai
Edward G. Michaelis: Charité - Universitätsmedizin
Amjad Khan: University of Oxford
Andrea Lau: Charité - Universitätsmedizin
Martin Schönlein: Charité - Universitätsmedizin
Anna Habringer: Kepler University Hospital
Josef Tomasits: Kepler University Hospital
Julia M. Adler: Freie Universität Berlin
Susanne Kimeswenger: Johannes Kepler University
Achim D. Gruber: Freie Universität Berlin
Wolfram Hoetzenecker: Johannes Kepler University
Herta Steinkellner: University of Natural Resources and Life Sciences
Bettina Purfürst: Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association
Reinhard Motz: Kepler University Hospital
Francesco Di Pierro: Velleja Research
Bernd Lamprecht: Johannes Kepler University
Nikolaus Osterrieder: Freie Universität Berlin
Markus Landthaler: Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association
Christian Drosten: Charité—Universitätsmedizin,
Adolfo García-Sastre: Icahn School of Medicine at Mount Sinai
Rupert Langer: Johannes Kepler University
Markus Ralser: Charité - Universitätsmedizin
Roland Eils: Charité - Universitätsmedizin and Berlin Institute of Health (BIH)
Maurice Reimann: Charité - Universitätsmedizin
Dorothy N. Y. Fan: Charité - Universitätsmedizin
Clemens A. Schmitt: Charité - Universitätsmedizin

Nature, 2021, vol. 599, issue 7884, 283-289

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41586-021-03995-1

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