2. Academic Validation
  3. SARS-CoV2 infection impairs the metabolism and redox function of cellular glutathione

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

  • Redox Biol. 2021 Sep;45:102041. doi: 10.1016/j.redox.2021.102041.
Desirée Bartolini 1,  Anna Maria Stabile 2,  Sabrina Bastianelli 3,  Daniela Giustarini 4,  Sara Pierucci 3,  Chiara Busti 3,  Carmine Vacca 5,  Anna Gidari 3,  Daniela Francisci 3,  Roberto Castronari 6,  Antonella Mencacci 6,  Manlio Di Cristina 5,  Riccardo Focaia 5,  Samuele Sabbatini 7,  Mario Rende 2,  Antimo Gioiello 8,  Gabriele Cruciani 5,  Ranieri Rossi 4,  Francesco Galli 9
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, University of Perugia, Nutrition and Clinical Biochemistry Lab, Via Del Giochetto, Monteluce, Perugia, Italy; Department of Medicine and Surgery, Section of Human, Clinical and Forensic Anatomy, School of Medicine, University of Perugia, P.le Lucio Severi, 1, Sant'Andrea Delle Fratte, 06132, Perugia, Italy.
  • 2 Department of Medicine and Surgery, Section of Human, Clinical and Forensic Anatomy, School of Medicine, University of Perugia, P.le Lucio Severi, 1, Sant'Andrea Delle Fratte, 06132, Perugia, Italy.
  • 3 Department of Medicine and Surgery, Clinic of Infectious Diseases, University of Perugia, Perugia, Italy.
  • 4 Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via A. Moro 2, I-53100, Siena, Italy.
  • 5 Department of Chemistry, Biology and Biotechnology, University of Perugia, Via Elce di Sotto 8, 06123, Perugia, Italy.
  • 6 Department of Medicine and Surgery, Microbiology Unit, University of Perugia, 06123, Perugia, Italy.
  • 7 Department of Medicine and Surgery, Medical Microbiology Section, University of Perugia, 06129, Perugia, Italy.
  • 8 Department of Pharmaceutical Sciences, University of Perugia, Nutrition and Clinical Biochemistry Lab, Via Del Giochetto, Monteluce, Perugia, Italy.
  • 9 Department of Pharmaceutical Sciences, University of Perugia, Nutrition and Clinical Biochemistry Lab, Via Del Giochetto, Monteluce, Perugia, Italy. Electronic address: francesco.galli@unipg.it.
PMID: 34146958 DOI: 10.1016/j.redox.2021.102041
Abstract

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.

Keywords

COVID-19; Glutathione; Nrf2; Protein glutathionylation; SARS-CoV-2; Thiols.

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