1. Pulmonary infection by SARS-CoV-2 induces senescence accompanied by an inflammatory phenotype in severe COVID-19: possible implications for viral mutagenesis
- Author
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Konstantinos Evangelou, Dimitris Veroutis, Koralia Paschalaki, Periklis G. Foukas, Nefeli Lagopati, Marios Dimitriou, Angelos Papaspyropoulos, Bindu Konda, Orsalia Hazapis, Aikaterini Polyzou, Sophia Havaki, Athanassios Kotsinas, Christos Kittas, Athanasios G. Tzioufas, Laurence de Leval, Demetris Vassilakos, Sotirios Tsiodras, Barry R. Stripp, Argyris Papantonis, Giovanni Blandino, Ioannis Karakasiliotis, Peter J. Barnes, and Vassilis G. Gorgoulis
- Subjects
Inflammation ,Pulmonary and Respiratory Medicine ,Phenotype ,Interleukin-6 ,Mutagenesis ,SARS-CoV-2 ,fungi ,COVID-19 ,Cytokines ,Humans ,Cellular Senescence ,Cytokines/metabolism ,Lung/metabolism ,Lung - Abstract
BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection of the respiratory system can progress to a multisystemic disease with aberrant inflammatory response. Cellular senescence promotes chronic inflammation, named senescence-associated secretory phenotype (SASP). We investigated whether coronavirus disease 2019 (COVID-19) is associated with cellular senescence and SASP.MethodsAutopsy lung tissue samples from 11 COVID-19 patients and 43 age-matched non-COVID-19 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 angiotensin-converting enzyme 2 and exhibited increased senescence (p16INK4A and SenTraGor positivity) and interleukin (IL)-1β and IL-6 expression. In vitro, infection of Vero-E6 cells with SARS-CoV-2 induced senescence (SenTraGor), 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 extrapulmonary 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.
- Published
- 2022