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.
Highlights
The current COVID-19 pandemic has illuminated the vulnerability of the elderly and those with chronic diseases to increased SARS-CoV-2-mediated mortality
We previously reported that SARS-CoV-2 surface antigen Spike-1 protein (S1), which signals through ACE2 receptors, can cause amplification of the tissuedestructive, pro-inflammatory senescence-associated secretory phenotype (SASP) of already senescent human cells [3]
We show that SARSCoV-2 Spike pseudotyped vesicular stomatitis virus (VSV) can cause nonsenescent cells to become senescent through Toll-like receptor-3 (TLR-3) in kidney endothelial and lung epithelial cells
Summary
The current COVID-19 pandemic has illuminated the vulnerability of the elderly and those with chronic diseases to increased SARS-CoV-2-mediated mortality. By August 2021, there had been over 207 million cases of SARS-CoV-2 and 4.3 million deaths worldwide (https://en.wikipedia.org/wiki/Template: COVID-19_pandemic_data accessed 08/16/2021). Those over age 65 accounted for 45% of patients hospitalized and 80% of those who died with SARSCoV-2 [1]. Recent studies have estimated that between 10-30% of patients experience persistent symptoms months after resolution of acute cases of COVID-19. These prolonged symptoms are referred to as postacute sequelae of SARS-CoV-2 infection (PASC) and might be a consequence of chronic inflammation induced during the acute phase of infection [2]. A mechanistic level of understanding of the short- and long-term effects of SARS-CoV-2 infection on cell and tissue function is urgently needed to tackle its acute and chronic adverse health outcomes
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