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

Authors

  • S. Lee
  • Y. Yu
  • J. Trimpert
  • F. Benthani
  • M. Mairhofer
  • P. Richter-Pechanska
  • E. Wyler
  • D. Belenki
  • S. Kaltenbrunner
  • M. Pammer
  • L. Kausche
  • T.C. Firsching
  • K. Dietert
  • M. Schotsaert
  • C. Martínez-Romero
  • G. Singh
  • S. Kunz
  • D. Niemeyer
  • R. Ghanem
  • H.J.F. Salzer
  • C. Paar
  • M. Mülleder
  • M. Uccellini
  • E.G. Michaelis
  • A. Khan
  • A. Lau
  • M. Schönlein
  • A. Habringer
  • J. Tomasits
  • J.M. Adler
  • S. Kimeswenger
  • A.D. Gruber
  • W. Hoetzenecker
  • H. Steinkellner
  • B. Purfuerst
  • R. Motz
  • F. Di Pierro
  • B. Lamprecht
  • N. Osterrieder
  • M. Landthaler
  • C. Drosten
  • A. García-Sastre
  • R. Langer
  • M. Ralser
  • R. Eils
  • M. Reimann
  • D.N.Y. Fan
  • C.A. Schmitt

Journal

  • Nature

Citation

  • Nature 599: 283–289

Abstract

  • Derailed cytokine and immune cell networks account for organ damage and clinical severity of COVID-19. 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 mediators. 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 tissue 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.


DOI

doi:10.1038/s41586-021-03995-1