title: Lung-specific expression of active Raf kinase results in increased mortality of influenza A virus-infected mice.
abstract: Alterations in signalling via the Raf/MEK/ERK pathway interfere with influenza A virus replication in cell culture. While virus yields are reduced in cells expressing dominant-negative Raf or ERK, virus propagation is enhanced upon expression of constitutively active Raf or MEK. To study the impact of active Raf on influenza virus propagation in vivo, we investigated transgenic mice expressing an activated mutant of c-Raf (Raf-BxB) in the main target tissue of influenza virus, the lung. Raf-BxB expression results in multicentric alveolar adenomas. Influenza virus A infection of Raf-BxB mice results in increased disease symptoms and higher mortality rates. The immune response against viral pathogens in transgenic animals did not differ from wild-type mice as determined by the use of a Pseudorabies virus (PRV) as a model for a viral infection not affecting the lung. No significant differences of influenza virus titers in the lung of Raf-BxB and wild-type mice were observed. However, immunohistology revealed increased numbers of influenza NP-positive cells in the alveolar linings of Raf-BxB mice, demonstrating the strong tropism of influenza virus for cells expressing active Raf. These findings disclose the possibility to use modified influenza virus for the therapy of tumors with an activated Ras/Raf signalling pathway.
authors.affiliation: Institut für Immunologie, Bundesforschungsanstalt für Viruskrankheiten der Tiere, Paul-Ehrlich-Str 28, Tübingen, Germany.
authors.forename: Veronika
authors.initials: V
authors.lastname: Olschläger
authors.forename: Stephan
authors.initials: S
authors.lastname: Pleschka
authors.forename: Timo
authors.initials: T
authors.lastname: Fischer
authors.forename: Hanns-Joachim
authors.initials: HJ
authors.lastname: Rziha
authors.forename: Walter
authors.initials: W
authors.lastname: Wurzer
authors.forename: Lothar
authors.initials: L
authors.lastname: Stitz
authors.forename: Ulf R
authors.initials: UR
authors.lastname: Rapp
authors.forename: Stephan
authors.initials: S
authors.lastname: Ludwig
authors.forename: Oliver
authors.initials: O
authors.lastname: Planz
mesh_terms: D000818:Animals; D002460:Cell Line; D004285:Dogs; D009980:Influenza A virus / Q000472:pathogenicity* / Q000502:physiology; D008168:Lung / Q000201:enzymology*; D051379:Mice; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism*; D013045:Species Specificity; D015996:Survival Rate; D014779:Virus Replication
chemical_list: D019908:Proto-Oncogene Proteins c-raf