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 INK4a+ 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.
【저자키워드】 COVID-19, SARS-CoV-2, senescence, toll like receptor 3, 【초록키워드】 coronavirus, clinical trial, spike, lung, amplification, Pseudotyped virus, cells, mice, morbidity, Patient, phenotype, Viral RNA, inhibitor, MHV, cellular senescence, mouse hepatitis virus, acute respiratory syndrome, Factor, causes, human cells, acute SARS-CoV-2 infection, Express, tlr-3, SASP, while, human cell, surface protein, pro-inflammatory, β-coronavirus, Cell, amplified, died, reported, amplify, increase, contribute, induce, prevented, senescent, inhibiting, exacerbate, senescent cell, was increased, 【제목키워드】 phenotype, tlr-3, human cell, cause, exacerbate,