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Gewählte Publikation:

Lee, S; Yu, Y; Trimpert, J; Benthani, F; Mairhofer, M; Richter-Pechanska, P; Wyler, E; Belenki, D; Kaltenbrunner, S; Pammer, M; Kausche, L; Firsching, TC; Dietert, K; Schotsaert, M; Martinez-Romero, C; Singh, G; Kunz, S; Niemeyer, D; Ghanem, R; Salzer, HJF; Paar, C; Mulleder, M; Uccellini, M; Michaelis, EG; Khan, A; Lau, A; Schonlein, M; Habringer, A; Tomasits, J; Adler, JM; Kimeswenger, S; Gruber, AD; Hoetzenecker, W; Steinkellner, H; Purfurst, B; Motz, R; Di Pierro, F; Lamprecht, B; Osterrieder, N; Landthaler, M; Drosten, C; Garcia-Sastre, A; Langer, R; Ralser, M; Eils, R; Reimann, M; Fan, DNY; Schmitt, CA.
(2021): Virus-induced senescence is a driver and therapeutic target in COVID-19
NATURE. 2021; 599(7884): 283-+. FullText FullText_BOKU

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 mediators(5-7). 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 tissue(1,8,9). 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. Virus-induced senescence is a central pathogenic feature in COVID-19, and senolytics, which promote apoptosis of senescent cells, can reduce disease severity in hamsters,mice, as well as humans infected with SARS-CoV-2.
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Steinkellner Herta
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