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| Item Type: | Article |
|---|---|
| Title: | Virus-induced senescence is driver and therapeutic target in COVID-19 |
| Creators: |
Lee, S.  ORCID: https://orcid.org/0000-0002-4614-2931, Yu, Y. ORCID: https://orcid.org/0000-0003-1928-2514, Trimpert, J. ORCID: https://orcid.org/0000-0003-1616-0810, Benthani, F. ORCID: https://orcid.org/0000-0002-3283-307X, Mairhofer, M., Richter-Pechanska, P. ORCID: https://orcid.org/0000-0001-6727-6317, Wyler, E. ORCID: https://orcid.org/0000-0002-9884-1806, Belenki, D. ORCID: https://orcid.org/0000-0002-9004-9849, Kaltenbrunner, S., Pammer, M., Kausche, L., Firsching, T.C. ORCID: https://orcid.org/0000-0003-1378-4951, Dietert, K., Schotsaert, M., Martínez-Romero, C. ORCID: https://orcid.org/0000-0001-8888-7715, Singh, G. ORCID: https://orcid.org/0000-0003-3260-2631, Kunz, S. ORCID: https://orcid.org/0000-0002-0131-3506, Niemeyer, D. ORCID: https://orcid.org/0000-0002-1897-6365, Ghanem, R., Salzer, H.J.F., Paar, C., Mülleder, M., Uccellini, M., Michaelis, E.G., Khan, A., Lau, A., Schönlein, M. ORCID: https://orcid.org/0000-0003-3156-3132, Habringer, A., Tomasits, J., Adler, J.M., Kimeswenger, S. ORCID: https://orcid.org/0000-0002-0443-8558, Gruber, A.D. ORCID: https://orcid.org/0000-0002-4502-0393, Hoetzenecker, W., Steinkellner, H., Purfuerst, B. ORCID: https://orcid.org/0000-0002-9887-7577, Motz, R., Di Pierro, F., Lamprecht, B. ORCID: https://orcid.org/0000-0003-3365-3449, Osterrieder, N., Landthaler, M. ORCID: https://orcid.org/0000-0002-1075-8734, Drosten, C. ORCID: https://orcid.org/0000-0001-7923-0519, García-Sastre, A. ORCID: https://orcid.org/0000-0002-6551-1827, Langer, R., Ralser, M., Eils, R. ORCID: https://orcid.org/0000-0002-0034-4036, Reimann, M. ORCID: https://orcid.org/0000-0002-7876-0128, Fan, D.N.Y. ORCID: https://orcid.org/0000-0001-6826-7076 and Schmitt, C.A. ORCID: https://orcid.org/0000-0002-4731-2226
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| 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: | Aniline Compounds, Animal Disease Models, Cell Line, Cellular Senescence, Dasatinib, Molecular Targeted Therapy, Quercetin, SARS-CoV-2, Sulfonamides, Thrombosis, Animals, Cricetina, Mice |
| Source: | Nature |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Volume: | 599 |
| Number: | 7884 |
| Page Range: | 283-289 |
| Date: | 11 November 2021 |
| Additional Information: | Copyright © 2021, The Author(s), under exclusive licence to Springer Nature Limited. - Erratum in: Nature 638(8052):E46. |
| Official Publication: | https://doi.org/10.1038/s41586-021-03995-1 |
| PubMed: | View item in PubMed |
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