Pulmonary infection by SARS-CoV-2 induces senescence accompanied by an inflammatory phenotype in severe COVID-19: possible implications for viral mutagenesis

Abstract

BackgroundSARS-CoV-2 infection of the respiratory system can progress to a multi-systemic disease with aberrant inflammatory response. Cellular senescence promotes chronic inflammation, named as senescence-associated secretory phenotype (SASP). We investigated whether COVID-19 disease is associated with cellular senescence and SASP.MethodsAutopsy lung tissue samples from 11 COVID-19 patients and 43 age-matched non-COVID controls with similar comorbidities were analysed by immunohistochemistry for SARS-CoV-2, markers of senescence and key SASP cytokines. Virally-induced senescence was functionally recapitulated in vitro, by infecting epithelial Vero-E6 cells and a three-dimensional alveosphere system of alveolar type 2 (AT2) cells with SARS-CoV-2 strains isolated from COVID-19 patients.ResultsSARS-CoV-2 was detected by immunocytochemistry and electron microscopy predominantly in AT2 cells. Infected AT2 cells expressed the angiotensin-converting-enzyme 2 (ACE2) and exhibited increased senescence (p16INK4A and SenTraGorTM positivity) and IL-1β and IL-6 expression. In vitro, infection of Vero-E6 cells with SARS-CoV-2 induced senescence (SenTraGorTM), DNA damage (γ-H2AX) and increased cytokine (IL-1β, IL-6, CXCL8) and Apolipoprotein B mRNA-editing (APOBEC) enzyme expression. Next-generation-sequencing analysis of progenies obtained from infected/senescent Vero-E6 cells demonstrated APOBEC-mediated SARS-CoV-2 mutations. Dissemination of the SARS-CoV-2-infection and senescence was confirmed in extra-pulmonary sites (kidney and liver) of a COVID-19 patient.ConclusionsWe demonstrate that in severe COVID-19, AT2 cells infected by SARS-CoV-2 exhibit senescence and a proinflammatory phenotype. In vitro, SARS-CoV-2 infection induces senescence and inflammation. Importantly, infected senescent cells may act as a source of SARS-CoV-2 mutagenesis mediated by APOBEC enzymes. Therefore, SARS-CoV-2-induced senescence may be an important molecular mechanism of severe COVID-19, disease persistence and mutagenesis.

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“…It is worth to report a recent excellent study on SARS-CoV-2 induced senescent cells as a fertile environment for viral mutagenesis, by Evangelou et al, Eur Respir J. 2022 [ 83 ].…”

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“…COVID-19 assay for BisD (tetrazole), BisD (nitrile), and NTV (PF07321332) were carried out by methods previously described [69] , [70] . Briefly, the cell culture assay was done as follows.…”

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“…Our knowledge of the mechanisms of action of the pandemic's causative agent, the human pathogenic coronavirus, SARS-CoV-2, has progressed at great speed since the onset of the pandemic, with resultant implications for clinical care and vaccination strategies. In this issue of the European Respiratory Journal, Evangelou et al outline the role of cellular senescence in the pathogenesis of severe clinical forms of COVID-19 [ 2 ].…”

“…The work of Evangelou et al ., [ 2 ] and others [ 16 , 18 , 19 ] contribute towards answering these questions, providing a significant contribution to understanding the role of senescence in the cytokine storm and severe multi-organ morbidity that has characterised severe clinical forms of COVID-19.…”