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) 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.
Ludwig
Stephan
S
Robert-Koch Institut, D-13353 Berlin, Germany. stephan.ludwig@uni-duesseldorf.de
Wolff
Thorsten
T
Ehrhardt
Christina
C
Wurzer
Walter Jürgen
WJ
Reinhardt
Jens
J
Planz
Oliver
O
Pleschka
Stephan
S
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D002460:Cell Line; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology; D014644:Genetic Variation; D009981:Influenza B virus / Q000235:genetics / Q000502:physiology*; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014779:Virus Replication
D004791:Enzyme Inhibitors; D019908:Proto-Oncogene Proteins c-raf; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases