Virus-induced senescence is a driver and therapeutic target in COVID-19

TY - JOUR

T1 - Virus-induced senescence is a driver and therapeutic target in COVID-19

AU - Lee, Soyoung

AU - Yu, Yong

AU - Trimpert, Jakob

AU - Benthani, Fahad

AU - Mairhofer, Mario

AU - Richter-Pechanska, Paulina

AU - Wyler, Emanuel

AU - Belenki, Dimitri

AU - Kaltenbrunner, Sabine

AU - Pammer, Maria

AU - Kausche, Lea

AU - Firsching, Theresa C

AU - Dietert, Kristina

AU - Schotsaert, Michael

AU - Martínez-Romero, Carles

AU - Singh, Gagandeep

AU - Kunz, Séverine

AU - Niemeyer, Daniela

AU - Ghanem, Riad

AU - Paar, Christian

AU - Mülleder, Michael

AU - Uccellini, Melissa

AU - Michaelis, Edward G

AU - Khan, Amjad

AU - Lau, Andrea

AU - Schönlein, Martin

AU - Habringer, Anna

AU - Tomasits, Josef

AU - Adler, Julia M

AU - Kimeswenger, Susanne

AU - Gruber, Achim D

AU - Hoetzenecker, Wolfram

AU - Steinkellner, Herta

AU - Purfürst, Bettina

AU - Motz, Reinhard

AU - Di Pierro, Francesco

AU - Lamprecht, Bernd

AU - Osterrieder, Nikolaus

AU - Landthaler, Markus

AU - Drosten, Christian

AU - García-Sastre, Adolfo

AU - Langer, Rupert

AU - Ralser, Markus

AU - Eils, Roland

AU - Reimann, Maurice

AU - Fan, Dorothy N Y

AU - Schmitt, Clemens A

N1 - © 2021. The Author(s), under exclusive licence to Springer Nature Limited.

PY - 2021/11

Y1 - 2021/11

N2 - 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.

AB - 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.

KW - Aniline Compounds/pharmacology

KW - Animals

KW - COVID-19/complications

KW - Cell Line

KW - Cellular Senescence/drug effects

KW - Cricetinae

KW - Dasatinib/pharmacology

KW - Disease Models, Animal

KW - Female

KW - Humans

KW - Male

KW - Mice

KW - Molecular Targeted Therapy

KW - Quercetin/pharmacology

KW - SARS-CoV-2/drug effects

KW - Sulfonamides/pharmacology

KW - Thrombosis/complications

U2 - 10.1038/s41586-021-03995-1

DO - 10.1038/s41586-021-03995-1

M3 - SCORING: Journal article

C2 - 34517409

VL - 599

SP - 283

EP - 289

JO - NATURE

JF - NATURE

SN - 0028-0836

IS - 7884

ER -