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Virus-induced senescence is a 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.
  • Lee S; Medical Department of Hematology, Oncology and Tumor Immunology, Molekulares Krebsforschungszentrum (MKFZ), Charité - Universitätsmedizin, Berlin, Germany.
  • Yu Y; Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
  • Trimpert J; Deutsches Konsortium für Translationale Krebsforschung (German Cancer Consortium), Partner Site Berlin, Berlin, Germany.
  • Benthani F; Medical Faculty, Johannes Kepler University, Linz, Austria.
  • Mairhofer M; Institute of Virology, Freie Universität Berlin, Berlin, Germany.
  • Richter-Pechanska P; Medical Faculty, Johannes Kepler University, Linz, Austria.
  • Wyler E; Medical Faculty, Johannes Kepler University, Linz, Austria.
  • Belenki D; Medical Department of Hematology, Oncology and Tumor Immunology, Molekulares Krebsforschungszentrum (MKFZ), Charité - Universitätsmedizin, Berlin, Germany.
  • Kaltenbrunner S; Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
  • Pammer M; Medical Department of Hematology, Oncology and Tumor Immunology, Molekulares Krebsforschungszentrum (MKFZ), Charité - Universitätsmedizin, Berlin, Germany.
  • Kausche L; Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
  • Firsching TC; Medical Faculty, Johannes Kepler University, Linz, Austria.
  • Dietert K; Medical Faculty, Johannes Kepler University, Linz, Austria.
  • Schotsaert M; Medical Department of Hematology, Oncology and Tumor Immunology, Molekulares Krebsforschungszentrum (MKFZ), Charité - Universitätsmedizin, Berlin, Germany.
  • Martínez-Romero C; Department of Hematology and Oncology, Kepler University Hospital, Linz, Austria.
  • Singh G; Institute of Veterinary Pathology, Freie Universität Berlin, Berlin, Germany.
  • Kunz S; Institute of Veterinary Pathology, Freie Universität Berlin, Berlin, Germany.
  • Niemeyer D; Veterinary Centre for Resistance Research, Freie Universität Berlin, Berlin, Germany.
  • Ghanem R; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Salzer HJF; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Paar C; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Mülleder M; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Uccellini M; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Michaelis EG; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Khan A; Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
  • Lau A; Institute of Virology, German Center for Infection Research (DZIF), Charité-Universitätsmedizin,, Berlin, Germany.
  • Schönlein M; Department of Hematology and Oncology, Kepler University Hospital, Linz, Austria.
  • Habringer A; Department of Pulmonology, Kepler University Hospital, Linz, Austria.
  • Tomasits J; Laboratory Medicine, Kepler University Hospital, Linz, Austria.
  • Adler JM; Core Facility - High-Throughput Mass Spectrometry and Department of Biochemistry, Charité - Universitätsmedizin, Berlin, Germany.
  • Kimeswenger S; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Gruber AD; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Hoetzenecker W; Regeneron Pharmaceuticals, New York, NY, USA.
  • Steinkellner H; Institute of Pathology, Charité - Universitätsmedizin, Berlin, Germany.
  • Purfürst B; Department of Chemistry, University of Oxford, Oxford, UK.
  • Motz R; Medical Department of Hematology, Oncology and Tumor Immunology, Molekulares Krebsforschungszentrum (MKFZ), Charité - Universitätsmedizin, Berlin, Germany.
  • Di Pierro F; Medical Department of Hematology, Oncology and Tumor Immunology, Molekulares Krebsforschungszentrum (MKFZ), Charité - Universitätsmedizin, Berlin, Germany.
  • Lamprecht B; Department of Oncology, Hematology and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Osterrieder N; Laboratory Medicine, Kepler University Hospital, Linz, Austria.
  • Landthaler M; Laboratory Medicine, Kepler University Hospital, Linz, Austria.
  • Drosten C; Institute of Virology, Freie Universität Berlin, Berlin, Germany.
  • García-Sastre A; Medical Faculty, Johannes Kepler University, Linz, Austria.
  • Langer R; Institute of Veterinary Pathology, Freie Universität Berlin, Berlin, Germany.
  • Ralser M; Medical Faculty, Johannes Kepler University, Linz, Austria.
  • Eils R; Department of Dermatology, Kepler University Hospital, Linz, Austria.
  • Reimann M; Department of Applied Genetics and Cell Biology, University of Natural Resources and Life Sciences, Vienna, Austria.
  • Fan DNY; Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
  • Schmitt CA; Institute of Pathology, Kepler University Hospital, Linz, Austria.
Nature ; 599(7884): 283-289, 2021 11.
Article in English | MEDLINE | ID: covidwho-1404888
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.
Subject(s)

Full text: Available Collection: International databases Database: MEDLINE Main subject: Cellular Senescence / Molecular Targeted Therapy / SARS-CoV-2 / COVID-19 Type of study: Prognostic study Topics: Long Covid Limits: Animals / Female / Humans / Male Language: English Journal: Nature Year: 2021 Document Type: Article Affiliation country: S41586-021-03995-1

Full text: Available Collection: International databases Database: MEDLINE Main subject: Cellular Senescence / Molecular Targeted Therapy / SARS-CoV-2 / COVID-19 Type of study: Prognostic study Topics: Long Covid Limits: Animals / Female / Humans / Male Language: English Journal: Nature Year: 2021 Document Type: Article Affiliation country: S41586-021-03995-1