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

Authors :
Lee, S.
Yu, Y.
Trimpert, J.
Benthani, F.
Mairhofer, M.
Richter-Pechanska, P.
Wyler, E.
Belenki, D.
Kaltenbrunner, S.
Pammer, M.
Kausche, L.
Firsching, T.C.
Dietert, K.
Schotsaert, M.
Martínez-Romero, C.
Singh, G.
Kunz, S.
Niemeyer, D.
Ghanem, R.
Salzer, H.J.F.
Paar, C.
Mülleder, M.
Uccellini, M.
Michaelis, E.G.
Khan, A.
Lau, A.
Schönlein, M.
Habringer, A.
Tomasits, J.
Adler, J.M.
Kimeswenger, S.
Gruber, A.D.
Hoetzenecker, W.
Steinkellner, H.
Purfuerst, B.
Motz, R.
Di Pierro, F.
Lamprecht, B.
Osterrieder, N.
Landthaler, M.
Drosten, C.
García-Sastre, A.
Langer, R.
Ralser, M.
Eils, R.
Reimann, M.
Fan, D.N.Y.
Schmitt, C.A.
Publication Year :
2021
Publisher :
Nature Publishing Group, 2021.

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.

Details

Language :
English
Database :
OpenAIRE
Accession number :
edsair.mdc......med..d4619bacb81aedfabac247bc3d59760f