Virus-induced senescence is a driver and therapeutic target in COVID-19
| Autor: | Markus Landthaler, Bernd Lamprecht, Riad Ghanem, Amjad Khan, Michael Mülleder, Maurice Reimann, Herta Steinkellner, Soyoung Lee, Emanuel Wyler, Mario Mairhofer, Wolfram Hoetzenecker, Paulina Richter-Pechanska, Séverine Kunz, Josef Tomasits, Rupert Langer, Kristina Dietert, Michael Schotsaert, Maria Pammer, Carles Martínez-Romero, Susanne Kimeswenger, Theresa C. Firsching, Jakob Trimpert, Melissa Uccellini, Achim D. Gruber, Bettina Purfürst, Adolfo García-Sastre, Clemens A. Schmitt, Reinhard Motz, Nikolaus Osterrieder, Anna Habringer, Markus Ralser, Julia Adler, Fahad Benthani, Martin Schönlein, Andrea Lau, Daniela Niemeyer, Christian Drosten, Dimitri Belenki, Dorothy N. Y. Fan, Roland Eils, Francesco Di Pierro, Lea Kausche, Gagandeep Singh, Christian Paar, Edward Georg Michaelis, Helmut J. F. Salzer, Yong Yu, Sabine Kaltenbrunner |
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| Rok vydání: | 2021 |
| Předmět: |
Senescence
Male medicine.medical_treatment Dasatinib Inflammation Biology Cell Line Mice Immune system Cricetinae medicine Macrophage Animals Humans Molecular Targeted Therapy Senolytic Cellular Senescence Sulfonamides Multidisciplinary Aniline Compounds SARS-CoV-2 fungi COVID-19 Thrombosis Neutrophil extracellular traps COVID-19 Drug Treatment Disease Models Animal Cytokine Apoptosis Cancer research Female Quercetin medicine.symptom |
| Zdroj: | Nature. 599(7884) |
| ISSN: | 1476-4687 |
| Popis: | 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. 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. |
| Databáze: | OpenAIRE |
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