RT Journal Article SR Electronic T1 Pulmonary infection by SARS-CoV-2 induces senescence accompanied by an inflammatory phenotype in severe COVID-19: possible implications for viral mutagenesis JF European Respiratory Journal JO Eur Respir J FD European Respiratory Society SP 2102951 DO 10.1183/13993003.02951-2021 VO 60 IS 2 A1 Evangelou, Konstantinos A1 Veroutis, Dimitris A1 Paschalaki, Koralia A1 Foukas, Periklis G. A1 Lagopati, Nefeli A1 Dimitriou, Marios A1 Papaspyropoulos, Angelos A1 Konda, Bindu A1 Hazapis, Orsalia A1 Polyzou, Aikaterini A1 Havaki, Sophia A1 Kotsinas, Athanassios A1 Kittas, Christos A1 Tzioufas, Athanasios G. A1 de Leval, Laurence A1 Vassilakos, Demetris A1 Tsiodras, Sotirios A1 Stripp, Barry R. A1 Papantonis, Argyris A1 Blandino, Giovanni A1 Karakasiliotis, Ioannis A1 Barnes, Peter J. A1 Gorgoulis, Vassilis G. YR 2022 UL https://publications.ersnet.org//content/60/2/2102951.abstract 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