The clinically approved proteasome inhibitor PS-341 efficiently blocks influenza A virus and vesicular stomatitis virus propagation by establishing an antiviral state.
Recently it has been shown that the proinflammatory NF-kappaB pathway promotes efficient influenza virus propagation. Based on these findings, it was suggested that NF-kappaB blockade may be a promising approach for antiviral intervention. The classical virus-induced activation of the NF-kappaB pathway requires proteasomal degradation of the inhibitor of NF-kappaB, IkappaB. Therefore, we hypothesized that inhibition of proteasomal IkappaB degradation should impair influenza A virus (IAV) replication. We chose the specific proteasome inhibitor PS-341, which is a clinically approved anticancer drug also known as Bortezomib or Velcade. As expected, PS-341 treatment of infected A549 cells in a concentration range that was not toxic resulted in a significant reduction of progeny virus titers. However, we could not observe the proposed suppression of NF-kappaB-signaling in vitro. Rather, PS-341 treatment resulted in an induction of IkappaB degradation and activation of NF-kappaB as well as the JNK/AP-1 pathway. This coincides with enhanced expression of antiviral genes, such as interleukin-6 and, most importantly, MxA, which is a strong interferon (IFN)-induced suppressor of influenza virus replication. This suggests that PS-341 may act as an antiviral agent via induction of the type I IFN response. Accordingly, PS-341 did not affect virus titers in Vero cells, which lack type I IFN genes, but strongly inhibited replication of vesicular stomatitis virus (VSV), a highly IFN-sensitive pathogen. Thus, we conclude that PS-341 blocks IAV and VSV replication by inducing an antiviral state mediated by the NF-kappaB-dependent expression of antivirus-acting gene products.
Dudek
Sabine Eva
SE
Institute of Molecular Virology, Centre for Molecular Biology of Inflammation, Muenster, Germany.
Luig
Christina
C
Pauli
Eva-Katharina
EK
Schubert
Ulrich
U
Ludwig
Stephan
S
D000998:Antiviral Agents / Q000494:pharmacology*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002460:Cell Line; D004847:Epithelial Cells / Q000821:virology; D019204:GTP-Binding Proteins / Q000096:biosynthesis; D006801:Humans; D009980:Influenza A virus / Q000187:drug effects*; D007370:Interferon Type I / Q000096:biosynthesis / Q000276:immunology; D015850:Interleukin-6 / Q000096:biosynthesis; D064547:Myxovirus Resistance Proteins; D011719:Pyrazines / Q000494:pharmacology*; D018116:Vesiculovirus / Q000187:drug effects*
D000998:Antiviral Agents; D001897:Boronic Acids; D007370:Interferon Type I; D015850:Interleukin-6; C579071:MX1 protein, human; D064547:Myxovirus Resistance Proteins; D011719:Pyrazines; D000069286:Bortezomib; D019204:GTP-Binding Proteins