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HDAC1-3 inhibition increases SARS-CoV-2 replication and productive infection in lung mesothelial and epithelial cells.
Trionfetti, Flavia; Alonzi, Tonino; Bontempi, Giulio; Terri, Michela; Battistelli, Cecilia; Montaldo, Claudia; Repele, Federica; Rotili, Dante; Valente, Sergio; Zwergel, Clemens; Matusali, Giulia; Maggi, Fabrizio; Goletti, Delia; Tripodi, Marco; Mai, Antonello; Strippoli, Raffaele.
Afiliação
  • Trionfetti F; Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
  • Alonzi T; Gene Expression Laboratory, National Institute for Infectious Diseases, Lazzaro Spallanzani IRCCS, Rome, Italy.
  • Bontempi G; Translational Research Unit, National Institute for Infectious Diseases "Lazzaro Spallanzani"-IRCCS, Rome, Italy.
  • Terri M; Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
  • Battistelli C; Gene Expression Laboratory, National Institute for Infectious Diseases, Lazzaro Spallanzani IRCCS, Rome, Italy.
  • Montaldo C; Gene Expression Laboratory, National Institute for Infectious Diseases, Lazzaro Spallanzani IRCCS, Rome, Italy.
  • Repele F; Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
  • Rotili D; Gene Expression Laboratory, National Institute for Infectious Diseases, Lazzaro Spallanzani IRCCS, Rome, Italy.
  • Valente S; Translational Research Unit, National Institute for Infectious Diseases "Lazzaro Spallanzani"-IRCCS, Rome, Italy.
  • Zwergel C; Department of Drug Chemistry and Technologies, Sapienza University of Rome, Rome, Italy.
  • Matusali G; Department of Drug Chemistry and Technologies, Sapienza University of Rome, Rome, Italy.
  • Maggi F; Department of Drug Chemistry and Technologies, Sapienza University of Rome, Rome, Italy.
  • Goletti D; Laboratory of Virology, National Institute for Infectious Diseases, Lazzaro Spallanzani IRCCS, Rome, Italy.
  • Tripodi M; Laboratory of Virology, National Institute for Infectious Diseases, Lazzaro Spallanzani IRCCS, Rome, Italy.
  • Mai A; Translational Research Unit, National Institute for Infectious Diseases "Lazzaro Spallanzani"-IRCCS, Rome, Italy.
  • Strippoli R; Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
Front Cell Infect Microbiol ; 13: 1257683, 2023.
Article em En | MEDLINE | ID: mdl-38162580
ABSTRACT

Background:

Despite the significant progress achieved in understanding the pathology and clinical management of SARS-CoV-2 infection, still pathogenic and clinical issues need to be clarified. Treatment with modulators of epigenetic targets, i.e., epidrugs, is a current therapeutic option in several cancers and could represent an approach in the therapy of viral diseases.

Results:

Aim of this study was the analysis of the role of histone deacetylase (HDAC) inhibition in the modulation of SARS-CoV-2 infection of mesothelial cells (MCs).MeT5A cells, a pleura MC line, were pre-treated with different specific class I and IIb HDAC inhibitors. Unexpectedly, treatment with HDAC1-3 inhibitors significantly increased ACE2/TMPRSS2 expression, suggesting a role in favoring SARS-CoV-2 infection. We focused our analysis on the most potent ACE2/TMPRSS2 inducer among the inhibitors analysed, MS-275, a HDAC1-3 inhibitor. ACE2/TMPRSS2 expression was validated by Western Blot (WB) and immunofluorescence. The involvement of HDAC inhibition in receptor induction was confirmed by HDAC1/HDAC2 silencing. In accordance to the ACE2/TMPRSS2 expression data, MS-275 increased SARS-CoV-2 replication and virus propagation in Vero E6 cells.Notably, MS-275 was able to increase ACE2/TMPRSS2 expression and SARS-CoV-2 production, although to a lesser extent, also in the lung adenocarcinoma cell line Calu-3 cells.Mechanistically, treatment with MS-275 increased H3 and H4 histone acetylation at ACE2/TMPRSS2 promoters, increasing their transcription.

Conclusion:

This study highlights a previously unrecognized effect of HDAC1-3 inhibition in increasing SARS-CoV-2 cell entry, replication and productive infection correlating with increased expression of ACE2 and TMPRSS2. These data, while adding basic insight into COVID-19 pathogenesis, warn for the use of HDAC inhibitors in SARS-CoV-2 patients.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: SARS-CoV-2 / COVID-19 Limite: Humans Idioma: En Revista: Front Cell Infect Microbiol Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Itália País de publicação: Suíça

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: SARS-CoV-2 / COVID-19 Limite: Humans Idioma: En Revista: Front Cell Infect Microbiol Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Itália País de publicação: Suíça