SARS-CoV-2 causes senescence in human cells and exacerbates the senescence-associated secretory phenotype through TLR-3
Senescent cells, which arise due to damage-associated signals, are apoptosis-resistant and can express a pro-inflammatory, tissue-destructive senescence-associated secretory phenotype (SASP). We recently reported that a component of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) surface protein, S1, can amplify the SASP of senescent cultured human cells and that a related mouse β-coronavirus, mouse hepatitis virus (MHV), increases SASP factors and senescent cell burden in infected mice. Here, we show that SARS-CoV-2 induces senescence in human non-senescent cells and exacerbates the SASP in human senescent cells through Toll-like receptor-3 (TLR-3). TLR-3, which senses viral RNA, was increased in human senescent compared to non-senescent cells. Notably, genetically or pharmacologically inhibiting TLR-3 prevented senescence induction and SASP amplification by SARS-CoV-2 or Spike pseudotyped virus. While an artificial TLR-3 agonist alone was not sufficient to induce senescence, it amplified the SASP in senescent human cells. Consistent with these findings, lung p16INK4a+ senescent cell burden was higher in patients who died from acute SARS-CoV-2 infection than other causes. Our results suggest that induction of cellular senescence and SASP amplification through TLR-3 contribute to SARS-CoV-2 morbidity, indicating that clinical trials of senolytics and/or SASP/TLR-3 inhibitors for alleviating acute and long-term SARS-CoV-2 sequelae are warranted.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:13 |
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| Enthalten in: |
Aging - 13(2021), 18 vom: 16. Sept., Seite 21838-21854 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Tripathi, Utkarsh [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 15.10.2021 Date Revised 03.04.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.18632/aging.203560 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM33073301X |
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| 245 | 1 | 0 | |a SARS-CoV-2 causes senescence in human cells and exacerbates the senescence-associated secretory phenotype through TLR-3 |
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| 500 | |a Date Completed 15.10.2021 | ||
| 500 | |a Date Revised 03.04.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Senescent cells, which arise due to damage-associated signals, are apoptosis-resistant and can express a pro-inflammatory, tissue-destructive senescence-associated secretory phenotype (SASP). We recently reported that a component of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) surface protein, S1, can amplify the SASP of senescent cultured human cells and that a related mouse β-coronavirus, mouse hepatitis virus (MHV), increases SASP factors and senescent cell burden in infected mice. Here, we show that SARS-CoV-2 induces senescence in human non-senescent cells and exacerbates the SASP in human senescent cells through Toll-like receptor-3 (TLR-3). TLR-3, which senses viral RNA, was increased in human senescent compared to non-senescent cells. Notably, genetically or pharmacologically inhibiting TLR-3 prevented senescence induction and SASP amplification by SARS-CoV-2 or Spike pseudotyped virus. While an artificial TLR-3 agonist alone was not sufficient to induce senescence, it amplified the SASP in senescent human cells. Consistent with these findings, lung p16INK4a+ senescent cell burden was higher in patients who died from acute SARS-CoV-2 infection than other causes. Our results suggest that induction of cellular senescence and SASP amplification through TLR-3 contribute to SARS-CoV-2 morbidity, indicating that clinical trials of senolytics and/or SASP/TLR-3 inhibitors for alleviating acute and long-term SARS-CoV-2 sequelae are warranted | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
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| 700 | 1 | |a Prata, Larissa G P Langhi |e verfasserin |4 aut | |
| 700 | 1 | |a Zhu, Yi |e verfasserin |4 aut | |
| 700 | 1 | |a Gerdes, Erin O Wissler |e verfasserin |4 aut | |
| 700 | 1 | |a Giorgadze, Nino |e verfasserin |4 aut | |
| 700 | 1 | |a Pirtskhalava, Tamar |e verfasserin |4 aut | |
| 700 | 1 | |a Parker, Erik |e verfasserin |4 aut | |
| 700 | 1 | |a Xue, Ailing |e verfasserin |4 aut | |
| 700 | 1 | |a Espindola-Netto, Jair Machado |e verfasserin |4 aut | |
| 700 | 1 | |a Stenger, Steffen |e verfasserin |4 aut | |
| 700 | 1 | |a Robbins, Paul D |e verfasserin |4 aut | |
| 700 | 1 | |a Niedernhofer, Laura J |e verfasserin |4 aut | |
| 700 | 1 | |a Dickinson, Stephanie L |e verfasserin |4 aut | |
| 700 | 1 | |a Allison, David B |e verfasserin |4 aut | |
| 700 | 1 | |a Kirchhoff, Frank |e verfasserin |4 aut | |
| 700 | 1 | |a Sparrer, Konstantin Maria Johannes |e verfasserin |4 aut | |
| 700 | 1 | |a Tchkonia, Tamar |e verfasserin |4 aut | |
| 700 | 1 | |a Kirkland, James L |e verfasserin |4 aut | |
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