COVID-19 Priority Research Paper Volume 13, Issue 18 pp 21838—21854
SARS-CoV-2 causes senescence in human cells and exacerbates the senescence-associated secretory phenotype through TLR-3
- 1 Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN 55905, USA
- 2 Institute of Molecular Virology, Ulm University Medical Center, Ulm 89081, Germany
- 3 Department of Physiology and Bioengineering, Mayo Clinic, Rochester, MN 55905, USA
- 4 Institute for Medical Microbiology and Hygiene, Ulm University Medical Center, Ulm 89081, Germany
- 5 Institute on the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA
- 6 Department of Epidemiology and Biostatistics, School of Public Health, Indiana University-Bloomington, Bloomington, IN 47405, USA
- 7 Division of General Internal Medicine, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA
Received: August 20, 2021 Accepted: September 14, 2021 Published: September 16, 2021
https://doi.org/10.18632/aging.203560How to Cite
Copyright: © 2021 Tripathi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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 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.