Evangelou, Konstantinos, Veroutis, Dimitris, Paschalaki, Koralia, Foukas, Periklis G., Lagopati, Nefeli, Dimitriou, Marios ORCID: 0000-0001-5699-2289, Papaspyropoulos, Angelos, Konda, Bindu, Hazapis, Orsalia, Polyzou, Aikaterini, Havaki, Sophia, Kotsinas, Athanassios, Kittas, Christos, Tzioufas, Athanasios G., De Leval, Laurence, Vassilakos, Demetris, Tsiodras, Sotirios, Stripp, Barry R., Papantonis, Argyris, Blandino, Giovanni, Karakasiliotis, Ioannis, Barnes, Peter J. and Gorgoulis, Vassilis G. (2022). Pulmonary infection by SARS-CoV-2 induces senescence accompanied by an inflammatory phenotype in severe COVID-19: possible implications for viral mutagenesis. Eur. Resp. J., 60 (2). SHEFFIELD: EUROPEAN RESPIRATORY SOC JOURNALS LTD. ISSN 1399-3003

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Abstract

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 (p16(INK4A) and SenTraGor positivity) and interleukin (IL)-1 beta and IL-6 expression. In vitro, infection of Vero-E6 cells with SARS-CoV-2 induced senescence (SenTraGor), DNA damage (gamma-H2AX) and increased cytokine (IL-1 beta, 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Evangelou, KonstantinosUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Veroutis, DimitrisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Paschalaki, KoraliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Foukas, Periklis G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lagopati, NefeliUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dimitriou, MariosUNSPECIFIEDorcid.org/0000-0001-5699-2289UNSPECIFIED
Papaspyropoulos, AngelosUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Konda, BinduUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hazapis, OrsaliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Polyzou, AikateriniUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Havaki, SophiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kotsinas, AthanassiosUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kittas, ChristosUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tzioufas, Athanasios G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
De Leval, LaurenceUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vassilakos, DemetrisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tsiodras, SotiriosUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stripp, Barry R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Papantonis, ArgyrisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Blandino, GiovanniUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Karakasiliotis, IoannisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Barnes, Peter J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gorgoulis, Vassilis G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-693560
DOI: 10.1183/13993003.02951-2021
Journal or Publication Title: Eur. Resp. J.
Volume: 60
Number: 2
Date: 2022
Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD
Place of Publication: SHEFFIELD
ISSN: 1399-3003
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CELLULAR SENESCENCE; EARLY-STAGE; QUERCETIN; APOPTOSIS; IMMUNITY; DISEASEMultiple languages
Respiratory SystemMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/69356

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