Pepstatin A alters host cell autophagic machinery and leads to a decrease in influenza A virus production

• Published in: Journal of cellular physiology Vol. 226; no. 12; pp. 3368 - 3377
• Main Authors: Matarrese, Paola, Nencioni, Lucia, Checconi, Paola, Ciarlo, Laura, Gambardella, Lucrezia, Ascione, Barbara, Sgarbanti, Rossella, Garaci, Enrico, Malorni, Walter, Palamara, Anna Teresa
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.12.2011
• Subjects: Antiviral Agents - pharmacology; Apoptosis - drug effects; Autophagy - drug effects; Cathepsin A - antagonists & inhibitors; Cathepsin A - metabolism; Cathepsin D - antagonists & inhibitors; Cathepsin D - metabolism; Cell Line, Tumor; Dipeptides - pharmacology; Down-Regulation; Host-Pathogen Interactions - drug effects; Humans; Influenza A Virus, H1N1 Subtype - drug effects; Influenza A Virus, H1N1 Subtype - growth & development; Influenza A Virus, H1N1 Subtype - pathogenicity; Lysosomes - drug effects; Lysosomes - enzymology; Lysosomes - virology; Membrane Potential, Mitochondrial - drug effects; Pepstatins - pharmacology; Protease Inhibitors - pharmacology; Time Factors; Viral Proteins - metabolism; Virus Replication - drug effects
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.22696

Autophagy is a survival mechanism that can take place in cells under metabolic stress and through which cells can recycle waste material. Disturbances in autophagic processes appear to be associated with a number of human pathologies, including viral infections. It has been hypothesized that viruses can subvert autophagy in order to penetrate the host cell and replicate. Because it has been suggested that autophagy is involved in influenza A virus replication, we analyzed the effects of two inhibitors of lysosomal proteases on the cellular control of influenza A virus replication. In particular, we used biochemical and morphological analyses to evaluate the modulation of influenza A/Puerto Rico/8/34 H1N1 virus production in the presence of CA074 and Pepstatin A, inhibitors of cathepsin proteases B and D, respectively. We found that Pepstatin A, but not CA074, significantly hindered influenza virus replication, probably by modulating host cell autophagic/apoptotic responses. These results are of potential interest to provide useful insights into the molecular pathways exploited by the influenza in order to replicate and to identify further cellular factors as targets for the development of innovative antiviral strategies. J. Cell. Physiol. 226: 3368–3377, 2011. © 2011 Wiley Periodicals, Inc.