Abstract
Reports of post-acute COVID-19 syndrome, in which the inflammatory response persists even after SARS-CoV-2 has disappeared, are increasing1, but the underlying mechanisms of post-acute COVID-19 syndrome remain unknown. Here, we show that SARS-CoV-2-infected cells trigger senescence-like cell-cycle arrest2,3 in neighboring uninfected cells in a paracrine manner via virus-induced cytokine production. In cultured human cells or bronchial organoids, these SASR-CoV-2 infection-induced senescent cells express high levels of a series of inflammatory factors known as senescence-associated secretory phenotypes (SASPs)4 in a sustained manner, even after SARS-CoV-2 is no longer detectable. We also show that the expression of the senescence marker CDKN2A (refs. 5,6) and various SASP factor4 genes is increased in the pulmonary cells of patients with severe post-acute COVID-19 syndrome. Furthermore, we find that mice exposed to a mouse-adapted strain of SARS-CoV-2 exhibit prolonged signs of cellular senescence and SASP in the lung at 14 days after infection when the virus was undetectable, which could be substantially reduced by the administration of senolytic drugs7. The sustained infection-induced paracrine senescence described here may be involved in the long-term inflammation caused by SARS-CoV-2 infection.
Highlights
Reports of post-acute COVID-19 syndrome, in which the inflammatory response persists even after SARS-CoV-2 has disappeared, are increasing[1], but the underlying mechanisms of post-acute COVID-19 syndrome remain unknown
We first set up a system to infect senescent cells with SARS-CoV-2 using primary normal human lung diploid fibroblasts (HDFs), which are commonly used in senescence studies[12]
When ACE2 was ectopically expressed in HDFs (ACE2-HDFs) to a level comparable to that in HepG2 cells, a human cancer cell line that can be infected with SARS-CoV-2, the HDFs became infectable with SARS-CoV-2 (Fig. 1b–d and Extended Data Fig. 1a,b)
Summary
Reports of post-acute COVID-19 syndrome, in which the inflammatory response persists even after SARS-CoV-2 has disappeared, are increasing[1], but the underlying mechanisms of post-acute COVID-19 syndrome remain unknown. The expression level of the ACE2 gene, which is required for SARS-CoV-2 to enter the cells, was increased severalfold upon the induction of cellular senescence in HDFs, as well as in other cultured primary normal human cells (Fig. 1a).
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