1. Virus-induced senescence is a driver and therapeutic target in COVID-19.
- Author
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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, Martínez-Romero C, Singh G, Kunz S, Niemeyer D, Ghanem R, Salzer HJF, Paar C, Mülleder M, Uccellini M, Michaelis EG, Khan A, Lau A, Schönlein M, Habringer A, Tomasits J, Adler JM, Kimeswenger S, Gruber AD, Hoetzenecker W, Steinkellner H, Purfürst 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 DNY, and Schmitt CA
- Subjects
- Aniline Compounds pharmacology, Aniline Compounds therapeutic use, Animals, COVID-19 complications, Cell Line, Cricetinae, Dasatinib pharmacology, Dasatinib therapeutic use, Disease Models, Animal, Female, Humans, Male, Mice, Quercetin pharmacology, Quercetin therapeutic use, SARS-CoV-2 drug effects, Sulfonamides pharmacology, Sulfonamides therapeutic use, Thrombosis complications, Thrombosis immunology, Thrombosis metabolism, COVID-19 pathology, COVID-19 virology, Cellular Senescence drug effects, Molecular Targeted Therapy, SARS-CoV-2 pathogenicity, COVID-19 Drug Treatment
- 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., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2021
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