SARS-CoV-2 infection triggers paracrine senescence and leads to a sustained senescence-associated inflammatory response (Hara Lab, in Nat Aging )

Reports of "post-acute COVID-19 syndrome," in which the inflammatory response persists even after SARS-CoV-2 has disappeared, are increasing 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 arrest 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), in a sustained manner, even after SARS-CoV-2 is no longer detectable.  We also show that the expression of the senescence marker CDKN2A and various SASP factor 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 post-infection when the virus was undetectable, which could be substantially reduced by the administration of senolytic drugs.  The sustained infection-induced paracrine senescence described here may be involved in the long-term inflammation caused by SARS-CoV-2 infection.


This article was published in Nature Aging on 25th, Jan-, 2022.

Title: SARS-CoV-2 infection triggers paracrine senescence and leads to a sustained senescence-associated inflammatory response

Authors: Shunya Tsuji, Shohei Minami, Rina Hashimoto, Yusuke Konishi, Tatsuya Suzuki, Tamae Kondo, Miwa Sasai, Shiho Torii, Chikako Ono, Shintaro Shichinohe, Shintaro Sato, Masahiro Wakita, Shintaro Okumura, Sosuke Nakano, Tatsuyuki Matsudaira, Tomonori Matsumoto, Shimpei Kawamoto, Masahiro Yamamoto, Tokiko Watanabe, Yoshiharu Matsuura, Kazuo Takayama, Takeshi Kobayashi, Toru Okamoto and Eiji Hara


  • Figure 1: Induction of cellular senescence by SARS-CoV-2 in human and mouse lung tissue
    (a) Single cell RNA sequence analysis of lungs from patients with Post-acute COVID-19
    (b) Effects of a Senolytic drug (ABT-263) on Balb/c mice infected with SARS-CoV-2(MA10) capable of infecting mice

  • Figure2: Induction of cellular senescence and persistence of inflammatory response by SARS-CoV-2