Abstract Aim: The aim of this study was to determine whether GSH-C4, a hydrophobic glutathione derivative, affects in vitro and in vivo influenza virus infection by interfering with redox-sensitive intracellular pathways involved in the maturation of viral hemagglutinin (HA). Results: GSH-C4 strongly inhibited influenza A virus replication in cultured cells and in lethally infected mice, where it also reduced lung damage and mortality. In cell-culture studies, GSH-C4 arrested viral HA folding; the disulfide-rich glycoprotein remained in the endoplasmic reticulum as a reduced monomer instead of undergoing oligomerization and cell plasma-membrane insertion. HA maturation depends on the host-cell oxidoreductase, protein disulfide isomerase (PDI), whose activity in infected cells is probably facilitated by virus-induced glutathione depletion. By correcting this deficit, GSH-C4 increased levels of reduced PDI and inhibited essential disulfide bond formation in HA. Host-cell glycoprotein expression in uninfected cells was unaffected by glutathione, which thus appears to act exclusively on glutathione-depleted cells. Innovation: All currently approved anti-influenza drugs target essential viral structures, and their efficacy is limited by toxicity and by the almost inevitable selection of drug-resistant viral mutants. GSH-C4 inhibits influenza virus replication by modulating redox-sensitive pathways in infected cells, without producing toxicity in uninfected cells or animals. Novel anti-influenza drugs that target intracellular pathways essential for viral replication ("cell-based approach") offer two important potential advantages: they are more difficult for the virus to adapt to and their efficacy should not be dependent on virus type, strain, or antigenic properties. Conclusion: Redox-sensitive host-cell pathways exploited for viral replication are promising targets for effective anti-influenza strategies. Antioxid. Redox Signal. 15, 000-000.

Sgarbanti, R., Nencioni, L., Amatore, D., Coluccio, P., Fraternale, A., Sale, P., et al. (2011). Redox Regulation of the Influenza Hemagglutinin Maturation Process: A New Cell-Mediated Strategy for Anti-Influenza Therapy. ANTIOXIDANTS & REDOX SIGNALING, 15(3), 593-606 [10.1089/ars.2010.3512].

Redox Regulation of the Influenza Hemagglutinin Maturation Process: A New Cell-Mediated Strategy for Anti-Influenza Therapy

CIRIOLO, MARIA ROSA;
2011-05-19

Abstract

Abstract Aim: The aim of this study was to determine whether GSH-C4, a hydrophobic glutathione derivative, affects in vitro and in vivo influenza virus infection by interfering with redox-sensitive intracellular pathways involved in the maturation of viral hemagglutinin (HA). Results: GSH-C4 strongly inhibited influenza A virus replication in cultured cells and in lethally infected mice, where it also reduced lung damage and mortality. In cell-culture studies, GSH-C4 arrested viral HA folding; the disulfide-rich glycoprotein remained in the endoplasmic reticulum as a reduced monomer instead of undergoing oligomerization and cell plasma-membrane insertion. HA maturation depends on the host-cell oxidoreductase, protein disulfide isomerase (PDI), whose activity in infected cells is probably facilitated by virus-induced glutathione depletion. By correcting this deficit, GSH-C4 increased levels of reduced PDI and inhibited essential disulfide bond formation in HA. Host-cell glycoprotein expression in uninfected cells was unaffected by glutathione, which thus appears to act exclusively on glutathione-depleted cells. Innovation: All currently approved anti-influenza drugs target essential viral structures, and their efficacy is limited by toxicity and by the almost inevitable selection of drug-resistant viral mutants. GSH-C4 inhibits influenza virus replication by modulating redox-sensitive pathways in infected cells, without producing toxicity in uninfected cells or animals. Novel anti-influenza drugs that target intracellular pathways essential for viral replication ("cell-based approach") offer two important potential advantages: they are more difficult for the virus to adapt to and their efficacy should not be dependent on virus type, strain, or antigenic properties. Conclusion: Redox-sensitive host-cell pathways exploited for viral replication are promising targets for effective anti-influenza strategies. Antioxid. Redox Signal. 15, 000-000.
19-mag-2011
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore BIO/10 - BIOCHIMICA
English
Sgarbanti, R., Nencioni, L., Amatore, D., Coluccio, P., Fraternale, A., Sale, P., et al. (2011). Redox Regulation of the Influenza Hemagglutinin Maturation Process: A New Cell-Mediated Strategy for Anti-Influenza Therapy. ANTIOXIDANTS & REDOX SIGNALING, 15(3), 593-606 [10.1089/ars.2010.3512].
Sgarbanti, R; Nencioni, L; Amatore, D; Coluccio, P; Fraternale, A; Sale, P; Mammola, C; Carpino, G; Gaudio, E; Magnani, M; Ciriolo, Mr; Garaci, E; Palamara, A
Articolo su rivista
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/14202
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 68
  • ???jsp.display-item.citation.isi??? 68
social impact