MEK inhibition impairs influenza B virus propagation without emergence of resistant variants

• Published in: FEBS letters 2004-03, Vol.561 (1), p.37-43
• Main Authors: Ludwig, Stephan, Wolff, Thorsten, Ehrhardt, Christina, Wurzer, Walter Jürgen, Reinhardt, Jens, Planz, Oliver, Pleschka, Stephan
• Format: Article
• Language: English
• Subjects: Active Transport, Cell Nucleus - drug effects; Animals; Cell Line; DMSO, dimethylsulfoxide; Dogs; Enzyme Inhibitors - pharmacology; ERK, extracellular signal-regulated kinase; Genetic Variation; Influenza B virus; Influenza B virus - genetics; Influenza B virus - physiology; Influenza virus; JNK, c-Jun NH2-terminal kinase; MAP Kinase Kinase 1; MAPK, mitogen-activated protein kinase; MDCK, Madin–Darby canine kidney; MEK, MAPK kinase/ERK kinase; Mitogen-activated protein kinase cascade; Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinase Kinases - metabolism; Mitogen-activated protein kinase/extracellular signal-regulated kinase inhibition; Mitogen-Activated Protein Kinases - genetics; Mitogen-Activated Protein Kinases - metabolism; Proto-Oncogene Proteins c-raf - genetics; Proto-Oncogene Proteins c-raf - metabolism; RNP, ribonucleoprotein complex; Signal Transduction; Viral resistance; Virus Replication
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/S0014-5793(04)00108-5

Influenza A and B viruses are still a major worldwide threat. We demonstrate that influenza B virus infection induces signaling via the Raf/MEK/ERK cascade, a process required for efficient virus production. Expression of dominant-negative Raf and ERK mutants or treatment with a MEK inhibitor (U0126) strongly impaired viral propagation, while selective activation of the pathway resulted in increased virus titers. MEK inhibition appears to interfere with a distinct viral nuclear export process. Most importantly, no resistant virus variants emerged in the presence of U0126 demonstrating that influenza viruses cannot easily adapt to the missing cellular function.