SARS-CoV-2 infects lung epithelial cells and induces senescence and an inflammatory response in patients with severe COVID-19

  1. Konstantinos Evangelou
  2. Dimitris Veroutis
  3. Periklis G. Foukas
  4. Koralia Paschalaki
  5. Nefeli Lagopati
  6. Marios Dimitriou
  7. Angelos Papaspyropoulos
  8. Orsalia Hazapis
  9. Aikaterini Polyzou
  10. Sophia Havaki
  11. Athanassios Kotsinas
  12. Christos Kittas
  13. Athanasios G. Tzioufas
  14. Laurence de Leval
  15. Demetris Vassilakos
  16. Sotirios Tsiodras
  17. Ioannis Karakasiliotis
  18. Peter J Barnes
  19. Vassilis G. Gorgoulis
1 evaluations Published on
Read the full article Related papers
This article on Sciety

Abstract

Rationale

SARS-CoV-2 infection of the respiratory system can progress to a life threatening multi-systemic disease, mediated via an excess of cytokines (“cytokine storm”), but the molecular mechanisms are poorly understood.

Objectives

To investigate whether SARS-CoV-2 may induce cellular senescence in lung epithelial cells, leading to secretion of inflammatory cytokines, known as the senescence-associated secretory phenotype (SASP).

Methods

Autopsy lung tissue samples from eleven COVID-19 patients and sixty age-matched non-infected controls were analysed by immunohistochemistry for SARS-CoV-2 and markers of cellular senescence (SenTraGor, p16 INK4A ) and key SASP cytokines (interleukin-1β, interleukin-6). We also investigated whether SARS-CoV-2 infection of an epithelial cell line induces senescence and cytokine secretion.

Measurements and Main Results

SARS-CoV-2 was detected by immunocytochemistry and electron microscopy predominantly in alveolar type-2 (AT2) cells, which also expressed the angiotensin-converting-enzyme 2 (ACE2), a critical entry receptor for this virus. In COVID-19 samples, AT2 cells displayed increased markers of senescence [p16 INK4A , SenTraGor staining positivity in 12±1.2% of cells compared to 1.7±0.13% in non-infected controls (p<0.001)], with markedly increased expression of interleukin-1β and interleukin-6 (p<0.001). Infection of epithelial cells (Vero E6) with SARS-CoV-2 in-vitro induced senescence and DNA damage (increased SenTraGor and γ-H2AX), and reduced proliferation (Ki67) compared to uninfected control cells (p<0.01).

Conclusions

We demonstrate that in severe COVID-19 patients, AT2 cells are infected with SARS-CoV-2 and show senescence and expression of proinflammatory cytokines. We also show that SARS-CoV-2 infection of epithelial cells may induce senescence and inflammation, indicating that cellular senescence may be an important molecular mechanism of severe COVID-19.

Related articles

Related articles are currently not available for this article.