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.
Bibliographical noteFunding Information:
This work was supported by NIH grants R37AG013925 (J.L.K., T.T.), P01AG062413 (J.L.K., T.T., L.J.N., P.D.R.), P30AG050886 and U24AG056053 (D.B.A.), the Connor Fund (J.L.K., T.T.), Robert P. and Arlene R. Kogod (J.L.K.), Robert J. and Theresa W. Ryan (J.L.K., T.T.), the Noaber Foundation (J.L.K., T.T.), DFG (German Research Foundation) CRC 1279, SPP 1923, SP1600/6-1 (F.K., K.M.J.S.), BMBF (Federal Ministry of Education and Research) Restrict SARS-CoV-2 (F.K.), and BMBF Junior Research group (IMMUNOMOD; K.M.J.S.).
© 2021. Tripathi et al. All Rights Reserved.
- toll like receptor 3
- COVID-19/drug therapy
- Toll-Like Receptor 3/metabolism
- Viral Proteins
- Cyclin-Dependent Kinase Inhibitor p16/metabolism
- Cellular Senescence
PubMed: MeSH publication types
- Research Support, Non-U.S. Gov't
- Journal Article
- Research Support, N.I.H., Extramural