Alveolar type II cells harbouring SARS-CoV-2 show senescence with a proinflammatory phenotype

Evangelou, K.; Veroutis, D.; Foukas, P. G.; Paschalaki, K.; Kittas, C.; Tzioufas, A. G.; de Leval, L.; Vassilakos, D.; Barnes, P. J.; Gorgoulis, V.

doi:10.1101/2021.01.02.424917

bioRxiv · 10.1101/2021.01.02.424917

Alveolar type II cells harbouring SARS-CoV-2 show senescence with a proinflammatory phenotype

Evangelou, K.·Veroutis, D.·Foukas, P. G.·Paschalaki, K.·Kittas, C.·Tzioufas, A. G.·de Leval, L.·Vassilakos, D.·Barnes, P. J.·Gorgoulis, V.

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Abstract

RationaleSARS-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. ObjectivesTo 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). MethodsAutopsy 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, p16INK4A) and key SASP cytokines (interleukin-1{beta}, interleukin-6). We also investigated whether SARS-CoV-2 infection of an epithelial cell line induces senescence and cytokine secretion. Measurements and Main ResultsSARS-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 [p16INK4A, 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-1{beta} 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 {gamma}-H2AX), and reduced proliferation (Ki67) compared to uninfected control cells (p<0.01). ConclusionsWe 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.

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Evangelou, K., Veroutis, D., Foukas, P. G., Paschalaki, K., Kittas, C., Tzioufas, A. G., de Leval, L., Vassilakos, D., Barnes, P. J., Gorgoulis, V.. 2021-01-02. Alveolar type II cells harbouring SARS-CoV-2 show senescence with a proinflammatory phenotype. https://doi.org/10.1101/2021.01.02.424917

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