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Nature
11, 2021;599 (7884): 283-289.

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, Clemens A Schmitt
Author Information
  1. Soyoung Lee: Medical Department of Hematology, Oncology and Tumor Immunology, Molekulares Krebsforschungszentrum (MKFZ), Charité - Universitätsmedizin, Berlin, Germany. ORCID
  2. Yong Yu: Medical Faculty, Johannes Kepler University, Linz, Austria.
  3. Jakob Trimpert: Institute of Virology, Freie Universität Berlin, Berlin, Germany. ORCID
  4. Fahad Benthani: Medical Faculty, Johannes Kepler University, Linz, Austria. ORCID
  5. Mario Mairhofer: Medical Faculty, Johannes Kepler University, Linz, Austria.
  6. Paulina Richter-Pechanska: Medical Department of Hematology, Oncology and Tumor Immunology, Molekulares Krebsforschungszentrum (MKFZ), Charité - Universitätsmedizin, Berlin, Germany.
  7. Emanuel Wyler: Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany. ORCID
  8. Dimitri Belenki: Medical Department of Hematology, Oncology and Tumor Immunology, Molekulares Krebsforschungszentrum (MKFZ), Charité - Universitätsmedizin, Berlin, Germany. ORCID
  9. Sabine Kaltenbrunner: Medical Faculty, Johannes Kepler University, Linz, Austria.
  10. Maria Pammer: Medical Faculty, Johannes Kepler University, Linz, Austria.
  11. Lea Kausche: Medical Department of Hematology, Oncology and Tumor Immunology, Molekulares Krebsforschungszentrum (MKFZ), Charité - Universitätsmedizin, Berlin, Germany.
  12. Theresa C Firsching: Institute of Veterinary Pathology, Freie Universität Berlin, Berlin, Germany. ORCID
  13. Kristina Dietert: Institute of Veterinary Pathology, Freie Universität Berlin, Berlin, Germany.
  14. Michael Schotsaert: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. ORCID
  15. Carles Martínez-Romero: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. ORCID
  16. Gagandeep Singh: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. ORCID
  17. Séverine Kunz: Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany. ORCID
  18. Daniela Niemeyer: Institute of Virology, German Center for Infection Research (DZIF), Charité-Universitätsmedizin,, Berlin, Germany. ORCID
  19. Riad Ghanem: Department of Hematology and Oncology, Kepler University Hospital, Linz, Austria.
  20. Helmut J F Salzer: Department of Pulmonology, Kepler University Hospital, Linz, Austria.
  21. Christian Paar: Laboratory Medicine, Kepler University Hospital, Linz, Austria.
  22. Michael Mülleder: Core Facility - High-Throughput Mass Spectrometry and Department of Biochemistry, Charité - Universitätsmedizin, Berlin, Germany.
  23. Melissa Uccellini: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  24. Edward G Michaelis: Institute of Pathology, Charité - Universitätsmedizin, Berlin, Germany.
  25. Amjad Khan: Department of Chemistry, University of Oxford, Oxford, UK.
  26. Andrea Lau: Medical Department of Hematology, Oncology and Tumor Immunology, Molekulares Krebsforschungszentrum (MKFZ), Charité - Universitätsmedizin, Berlin, Germany.
  27. Martin Schönlein: Medical Department of Hematology, Oncology and Tumor Immunology, Molekulares Krebsforschungszentrum (MKFZ), Charité - Universitätsmedizin, Berlin, Germany.
  28. Anna Habringer: Laboratory Medicine, Kepler University Hospital, Linz, Austria.
  29. Josef Tomasits: Laboratory Medicine, Kepler University Hospital, Linz, Austria.
  30. Julia M Adler: Institute of Virology, Freie Universität Berlin, Berlin, Germany.
  31. Susanne Kimeswenger: Medical Faculty, Johannes Kepler University, Linz, Austria. ORCID
  32. Achim D Gruber: Institute of Veterinary Pathology, Freie Universität Berlin, Berlin, Germany. ORCID
  33. Wolfram Hoetzenecker: Medical Faculty, Johannes Kepler University, Linz, Austria.
  34. Herta Steinkellner: Department of Applied Genetics and Cell Biology, University of Natural Resources and Life Sciences, Vienna, Austria.
  35. Bettina Purfürst: Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
  36. Reinhard Motz: Institute of Pathology, Kepler University Hospital, Linz, Austria.
  37. Francesco Di Pierro: Scientific and Research Department, Velleja Research, Milan, Italy.
  38. Bernd Lamprecht: Medical Faculty, Johannes Kepler University, Linz, Austria. ORCID
  39. Nikolaus Osterrieder: Institute of Virology, Freie Universität Berlin, Berlin, Germany.
  40. Markus Landthaler: Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany. ORCID
  41. Christian Drosten: Institute of Virology, German Center for Infection Research (DZIF), Charité-Universitätsmedizin,, Berlin, Germany. ORCID
  42. Adolfo García-Sastre: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. ORCID
  43. Rupert Langer: Medical Faculty, Johannes Kepler University, Linz, Austria.
  44. Markus Ralser: Core Facility - High-Throughput Mass Spectrometry and Department of Biochemistry, Charité - Universitätsmedizin, Berlin, Germany.
  45. Roland Eils: Center for Digital Health, Charité - Universitätsmedizin and Berlin Institute of Health (BIH), Berlin, Germany. ORCID
  46. Maurice Reimann: Medical Department of Hematology, Oncology and Tumor Immunology, Molekulares Krebsforschungszentrum (MKFZ), Charité - Universitätsmedizin, Berlin, Germany.
  47. Dorothy N Y Fan: Medical Department of Hematology, Oncology and Tumor Immunology, Molekulares Krebsforschungszentrum (MKFZ), Charité - Universitätsmedizin, Berlin, Germany.
  48. Clemens A Schmitt: Medical Department of Hematology, Oncology and Tumor Immunology, Molekulares Krebsforschungszentrum (MKFZ), Charité - Universitätsmedizin, Berlin, Germany. clemens.schmitt@charite.de. ORCID
PMID: 34517409 DOI: 10.1038/s41586-021-03995-1

Abstract

Derailed cytokine and immune cell networks account for the organ damage and the clinical severity of COVID-19 (refs. ). 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 mediators. 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 tissue. 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.

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Grants

  1. FC001134/Wellcome Trust
  2. U19 AI142733/NIAID NIH HHS
  3. U19 AI135972/NIAID NIH HHS

MeSH Term

Aniline Compounds
Animals
COVID-19
Cell Line
Cellular Senescence
Cricetinae
Dasatinib
Disease Models, Animal
Female
Humans
Male
Mice
Molecular Targeted Therapy
Quercetin
SARS-CoV-2
Sulfonamides
Thrombosis
COVID-19 Drug Treatment

Chemicals

Aniline Compounds
Sulfonamides
Quercetin
Dasatinib
navitoclax
Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Links to CNCB-NGDC Resources

GEN: GEND000362 (Virus-induced senescence is a central pathogenic principle and therapeutic target in COVID-19 disease)

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