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SARS-CoV2 infection impairs the metabolism and redox function of cellular glutathione

Viral infections sustain their replication cycle promoting a pro-oxidant environment in the host cell. In this context, specific alterations of the levels and homeostatic function of the tripeptide glutathione have been reported to play a causal role in the pro-oxidant and cytopathic effects (CPE) o...

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Autores principales: Bartolini, Desirée, Stabile, Anna Maria, Bastianelli, Sabrina, Giustarini, Daniela, Pierucci, Sara, Busti, Chiara, Vacca, Carmine, Gidari, Anna, Francisci, Daniela, Castronari, Roberto, Mencacci, Antonella, Di Cristina, Manlio, Focaia, Riccardo, Sabbatini, Samuele, Rende, Mario, Gioiello, Antimo, Cruciani, Gabriele, Rossi, Ranieri, Galli, Francesco
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190457/
https://www.ncbi.nlm.nih.gov/pubmed/34146958
http://dx.doi.org/10.1016/j.redox.2021.102041
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author Bartolini, Desirée
Stabile, Anna Maria
Bastianelli, Sabrina
Giustarini, Daniela
Pierucci, Sara
Busti, Chiara
Vacca, Carmine
Gidari, Anna
Francisci, Daniela
Castronari, Roberto
Mencacci, Antonella
Di Cristina, Manlio
Focaia, Riccardo
Sabbatini, Samuele
Rende, Mario
Gioiello, Antimo
Cruciani, Gabriele
Rossi, Ranieri
Galli, Francesco
author_facet Bartolini, Desirée
Stabile, Anna Maria
Bastianelli, Sabrina
Giustarini, Daniela
Pierucci, Sara
Busti, Chiara
Vacca, Carmine
Gidari, Anna
Francisci, Daniela
Castronari, Roberto
Mencacci, Antonella
Di Cristina, Manlio
Focaia, Riccardo
Sabbatini, Samuele
Rende, Mario
Gioiello, Antimo
Cruciani, Gabriele
Rossi, Ranieri
Galli, Francesco
author_sort Bartolini, Desirée
collection PubMed
description Viral infections sustain their replication cycle promoting a pro-oxidant environment in the host cell. In this context, specific alterations of the levels and homeostatic function of the tripeptide glutathione have been reported to play a causal role in the pro-oxidant and cytopathic effects (CPE) of the virus. In this study, these aspects were investigated for the first time in SARS-CoV2-infected Vero E6 cells, a reliable and well-characterized in vitro model of this infection. SARS-CoV2 markedly decreased the levels of cellular thiols, essentially lowering the reduced form of glutathione (GSH). Such an important defect occurred early in the CPE process (in the first 24 hpi). Thiol analysis in N-acetyl-Cys (NAC)-treated cells and membrane transporter expression data demonstrated that both a lowered uptake of the GSH biosynthesis precursor Cys and an increased efflux of cellular thiols, could play a role in this context. Increased levels of oxidized glutathione (GSSG) and protein glutathionylation were also observed along with upregulation of the ER stress marker PERK. The antiviral drugs Remdesivir (Rem) and Nelfinavir (Nel) influenced these changes at different levels, essentially confirming the importance or blocking viral replication to prevent GSH depletion in the host cell. Accordingly, Nel, the most potent antiviral in our in vitro study, produced a timely activation of Nrf2 transcription factor and a GSH enhancing response that synergized with NAC to restore GSH levels in the infected cells. Despite poor in vitro antiviral potency and GSH enhancing function, Rem treatment was found to prevent the SARS-CoV2-induced glutathionylation of cellular proteins. In conclusion, SARS-CoV2 infection impairs the metabolism of cellular glutathione. NAC and the antiviral Nel can prevent such defect in vitro.
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spelling pubmed-81904572021-06-10 SARS-CoV2 infection impairs the metabolism and redox function of cellular glutathione Bartolini, Desirée Stabile, Anna Maria Bastianelli, Sabrina Giustarini, Daniela Pierucci, Sara Busti, Chiara Vacca, Carmine Gidari, Anna Francisci, Daniela Castronari, Roberto Mencacci, Antonella Di Cristina, Manlio Focaia, Riccardo Sabbatini, Samuele Rende, Mario Gioiello, Antimo Cruciani, Gabriele Rossi, Ranieri Galli, Francesco Redox Biol Research Paper Viral infections sustain their replication cycle promoting a pro-oxidant environment in the host cell. In this context, specific alterations of the levels and homeostatic function of the tripeptide glutathione have been reported to play a causal role in the pro-oxidant and cytopathic effects (CPE) of the virus. In this study, these aspects were investigated for the first time in SARS-CoV2-infected Vero E6 cells, a reliable and well-characterized in vitro model of this infection. SARS-CoV2 markedly decreased the levels of cellular thiols, essentially lowering the reduced form of glutathione (GSH). Such an important defect occurred early in the CPE process (in the first 24 hpi). Thiol analysis in N-acetyl-Cys (NAC)-treated cells and membrane transporter expression data demonstrated that both a lowered uptake of the GSH biosynthesis precursor Cys and an increased efflux of cellular thiols, could play a role in this context. Increased levels of oxidized glutathione (GSSG) and protein glutathionylation were also observed along with upregulation of the ER stress marker PERK. The antiviral drugs Remdesivir (Rem) and Nelfinavir (Nel) influenced these changes at different levels, essentially confirming the importance or blocking viral replication to prevent GSH depletion in the host cell. Accordingly, Nel, the most potent antiviral in our in vitro study, produced a timely activation of Nrf2 transcription factor and a GSH enhancing response that synergized with NAC to restore GSH levels in the infected cells. Despite poor in vitro antiviral potency and GSH enhancing function, Rem treatment was found to prevent the SARS-CoV2-induced glutathionylation of cellular proteins. In conclusion, SARS-CoV2 infection impairs the metabolism of cellular glutathione. NAC and the antiviral Nel can prevent such defect in vitro. Elsevier 2021-06-10 /pmc/articles/PMC8190457/ /pubmed/34146958 http://dx.doi.org/10.1016/j.redox.2021.102041 Text en © 2021 The Authors. Published by Elsevier B.V. https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Paper
Bartolini, Desirée
Stabile, Anna Maria
Bastianelli, Sabrina
Giustarini, Daniela
Pierucci, Sara
Busti, Chiara
Vacca, Carmine
Gidari, Anna
Francisci, Daniela
Castronari, Roberto
Mencacci, Antonella
Di Cristina, Manlio
Focaia, Riccardo
Sabbatini, Samuele
Rende, Mario
Gioiello, Antimo
Cruciani, Gabriele
Rossi, Ranieri
Galli, Francesco
SARS-CoV2 infection impairs the metabolism and redox function of cellular glutathione
title SARS-CoV2 infection impairs the metabolism and redox function of cellular glutathione
title_full SARS-CoV2 infection impairs the metabolism and redox function of cellular glutathione
title_fullStr SARS-CoV2 infection impairs the metabolism and redox function of cellular glutathione
title_full_unstemmed SARS-CoV2 infection impairs the metabolism and redox function of cellular glutathione
title_short SARS-CoV2 infection impairs the metabolism and redox function of cellular glutathione
title_sort sars-cov2 infection impairs the metabolism and redox function of cellular glutathione
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190457/
https://www.ncbi.nlm.nih.gov/pubmed/34146958
http://dx.doi.org/10.1016/j.redox.2021.102041
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