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

Item Type:Article
Title:Virus-induced senescence is driver and therapeutic target in COVID-19
Creators Name:Lee, S. and Yu, Y. and Trimpert, J. and Benthani, F. and Mairhofer, M. and Richter-Pechanska, P. and Wyler, E. and Belenki, D. and Kaltenbrunner, S. and Pammer, M. and Kausche, L. and Firsching, T.C. and Dietert, K. and Schotsaert, M. and Martínez-Romero, C. and Singh, G. and Kunz, S. and Niemeyer, D. and Ghanem, R. and Salzer, H.J.F. and Paar, C. and Mülleder, M. and Uccellini, M. and Michaelis, E.G. and Khan, A. and Lau, A. and Schönlein, M. and Habringer, A. and Tomasits, J. and Adler, J.M. and Kimeswenger, S. and Gruber, A.D. and Hoetzenecker, W. and Steinkellner, H. and Purfuerst, B. and Motz, R. and Di Pierro, F. and Lamprecht, B. and Osterrieder, N. and Landthaler, M. and Drosten, C. and García-Sastre, A. and Langer, R. and Ralser, M. and Eils, R. and Reimann, M. and Fan, D.N.Y. and Schmitt, C.A.
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.
Keywords:Animals, Cricetinae, Mesocricetus auratus, Mice, Phodopus
Source:Nature
ISSN:0028-0836
Publisher:Nature Publishing Group
Date:13 September 2021
Official Publication:https://doi.org/10.1038/s41586-021-03995-1
PubMed:View item in PubMed

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