PT - JOURNAL ARTICLE AU - Evangelou, Konstantinos AU - Veroutis, Dimitris AU - Paschalaki, Koralia AU - Foukas, Periklis G. AU - Lagopati, Nefeli AU - Dimitriou, Marios AU - Papaspyropoulos, Angelos AU - Konda, Bindu AU - Hazapis, Orsalia AU - Polyzou, Aikaterini AU - Havaki, Sophia AU - Kotsinas, Athanassios AU - Kittas, Christos AU - Tzioufas, Athanasios G. AU - de Leval, Laurence AU - Vassilakos, Demetris AU - Tsiodras, Sotirios AU - Stripp, Barry R. AU - Papantonis, Argyris AU - Blandino, Giovanni AU - Karakasiliotis, Ioannis AU - Barnes, Peter J. AU - Gorgoulis, Vassilis G. TI - Pulmonary infection by SARS-CoV-2 induces senescence accompanied by an inflammatory phenotype in severe COVID-19: possible implications for viral mutagenesis AID - 10.1183/13993003.02951-2021 DP - 2022 Aug 01 TA - European Respiratory Journal PG - 2102951 VI - 60 IP - 2 4099 - https://publications.ersnet.org//content/60/2/2102951.short 4100 - https://publications.ersnet.org//content/60/2/2102951.full SO - Eur Respir J2022 Aug 01; 60 AB - Background Severe 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.Methods Autopsy 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.Results SARS-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.Conclusions We 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.In severe COVID-19, alveolar type 2 (AT2) cells infected by SARS-CoV-2 exhibit senescence accompanied by a proinflammatory phenotype, a molecular mechanism that may be important in persistence of disease (post-acute sequelae of COVID-19) and mutagenesis https://bit.ly/3fnopg9