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

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...

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Bibliographic Details
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
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Summary: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.
ISSN:0014-5793
1873-3468
DOI:10.1016/S0014-5793(04)00108-5