1. Virus-induced senescence is driver and therapeutic target in COVID-19
- Author
-
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., and Schmitt, C.A.
- Subjects
Cancer Research ,Technology Platforms - 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.
- Published
- 2021