TY - JOUR
T1 - SARS-CoV-2 causes senescence in human cells and exacerbates the senescence-associated secretory phenotype through TLR-3
AU - Tripathi, Utkarsh
AU - Nchioua, Rayhane
AU - Prata, Larissa G.P.Langhi
AU - Zhu, Yi
AU - Gerdes, Erin O.Wissler
AU - Giorgadze, Nino
AU - Pirtskhalava, Tamar
AU - Parker, Erik
AU - Xue, Ailing
AU - Espindola-Netto, Jair Machado
AU - Stenger, Steffen
AU - Robbins, Paul D.
AU - Niedernhofer, Laura J.
AU - Dickinson, Stephanie L.
AU - Allison, David B.
AU - Kirchhoff, Frank
AU - Sparrer, Konstantin Maria Johannes
AU - Tchkonia, Tamar
AU - Kirkland, James L.
N1 - Publisher Copyright:
© 2021. Tripathi et al. All Rights Reserved.
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
KW - COVID-19
KW - SARS-COV-2
KW - senescence
KW - toll like receptor 3
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U2 - 10.18632/aging.203560
DO - 10.18632/aging.203560
M3 - Article
C2 - 34531331
AN - SCOPUS:85116402714
SN - 1945-4589
VL - 13
SP - 21838
EP - 21854
JO - Aging
JF - Aging
IS - 18
ER -