title: Pepstatin A alters host cell autophagic machinery and leads to a decrease in influenza A virus production.
abstract: 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.
authors.affiliation: Department of Drug Research and Medicine Evaluation, Istituto Superiore di Sanita', Rome, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Matarrese
authors.forename: Lucia
authors.initials: L
authors.lastname: Nencioni
authors.forename: Paola
authors.initials: P
authors.lastname: Checconi
authors.forename: Laura
authors.initials: L
authors.lastname: Ciarlo
authors.forename: Lucrezia
authors.initials: L
authors.lastname: Gambardella
authors.forename: Barbara
authors.initials: B
authors.lastname: Ascione
authors.forename: Rossella
authors.initials: R
authors.lastname: Sgarbanti
authors.forename: Enrico
authors.initials: E
authors.lastname: Garaci
authors.forename: Walter
authors.initials: W
authors.lastname: Malorni
authors.forename: Anna Teresa
authors.initials: AT
authors.lastname: Palamara
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D043402:Cathepsin A / Q000037:antagonists & inhibitors / Q000378:metabolism; D002402:Cathepsin D / Q000037:antagonists & inhibitors / Q000378:metabolism; D045744:Cell Line, Tumor; D004151:Dipeptides / Q000494:pharmacology; D015536:Down-Regulation; D054884:Host-Pathogen Interactions / Q000187:drug effects; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects* / Q000254:growth & development / Q000472:pathogenicity; D008247:Lysosomes / Q000187:drug effects* / Q000201:enzymology / Q000821:virology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D010436:Pepstatins / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology*; D013997:Time Factors; D014764:Viral Proteins / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; C400541:CA 074 methyl ester; D004151:Dipeptides; D010436:Pepstatins; D011480:Protease Inhibitors; D014764:Viral Proteins; C468629:CTSA protein, human; D043402:Cathepsin A; C533922:CTSD protein, human; D002402:Cathepsin D; C031375:pepstatin