tetano
Editor, Senior Moderator
Aging (Albany NY)
. 2021 Sep 16;12(undefined).
doi: 10.18632/aging.203560. Online ahead of print.
SARS-CoV-2 causes senescence in human cells and exacerbates the senescence-associated secretory phenotype through TLR-3
Utkarsh Tripathi[SUP] 1 [/SUP], Rayhane Nchioua[SUP] 2 [/SUP], Larissa G P Langhi Prata[SUP] 1 [/SUP], Yi Zhu[SUP] 1 3 [/SUP], Erin O Wissler Gerdes[SUP] 1 [/SUP], Nino Giorgadze[SUP] 1 [/SUP], Tamar Pirtskhalava[SUP] 1 [/SUP], Erik Parker[SUP] 4 [/SUP], Ailing Xue[SUP] 1 [/SUP], Jair Machado Espindola-Netto[SUP] 1 [/SUP], Steffen Stenger[SUP] 5 [/SUP], Paul D Robbins[SUP] 6 [/SUP], Laura J Niedernhofer[SUP] 6 [/SUP], Stephanie L Dickinson[SUP] 4 [/SUP], David B Allison[SUP] 4 [/SUP], Frank Kirchhoff[SUP] 2 [/SUP], Konstantin Maria Johannes Sparrer[SUP] 2 [/SUP], Tamar Tchkonia[SUP] 1 3 [/SUP], James L Kirkland[SUP] 1 3 7 [/SUP]
Affiliations
Abstract
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 p16[SUP]INK4a+[/SUP] 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.
Keywords: COVID-19; SARS-COV-2; senescence; toll like receptor 3.
. 2021 Sep 16;12(undefined).
doi: 10.18632/aging.203560. Online ahead of print.
SARS-CoV-2 causes senescence in human cells and exacerbates the senescence-associated secretory phenotype through TLR-3
Utkarsh Tripathi[SUP] 1 [/SUP], Rayhane Nchioua[SUP] 2 [/SUP], Larissa G P Langhi Prata[SUP] 1 [/SUP], Yi Zhu[SUP] 1 3 [/SUP], Erin O Wissler Gerdes[SUP] 1 [/SUP], Nino Giorgadze[SUP] 1 [/SUP], Tamar Pirtskhalava[SUP] 1 [/SUP], Erik Parker[SUP] 4 [/SUP], Ailing Xue[SUP] 1 [/SUP], Jair Machado Espindola-Netto[SUP] 1 [/SUP], Steffen Stenger[SUP] 5 [/SUP], Paul D Robbins[SUP] 6 [/SUP], Laura J Niedernhofer[SUP] 6 [/SUP], Stephanie L Dickinson[SUP] 4 [/SUP], David B Allison[SUP] 4 [/SUP], Frank Kirchhoff[SUP] 2 [/SUP], Konstantin Maria Johannes Sparrer[SUP] 2 [/SUP], Tamar Tchkonia[SUP] 1 3 [/SUP], James L Kirkland[SUP] 1 3 7 [/SUP]
Affiliations
- PMID: 34531331
- DOI: 10.18632/aging.203560
Abstract
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 p16[SUP]INK4a+[/SUP] 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.
Keywords: COVID-19; SARS-COV-2; senescence; toll like receptor 3.