Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Lung-specific expression of active Raf kinase results in increased mortality of influenza A virus-infected mice

Oncogene volume 23, pages 6639–6646 (2004)Cite this article

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  • Anderson H, Petrie K, Berrisford C, Charlett A, Thatcher N and Zambon M . (1999). Br. J. Cancer, 80, 219–220.

  • Arrowood JR and Hayney MS . (2002). Ann. Pharmacother., 36, 1219–1229.

  • Bergmann M, Romirer I, Sachet M, Fleischhacker R, Garcia-Sastre A, Palese P, Wolff K, Pehamberger H, Jakesz R and Muster T . (2001). Cancer Res., 61, 8188–8193.

  • Bos JL . (1989). Cancer Res., 49, 4682–4689.

  • Brydak LB and Machala M . (2000). Drugs, 60, 35–53.

  • Card JP and Enquist LW . (1995). Crit. Rev. Neurobiol., 9, 137–162.

  • Couch RB, Englund JA and Whimbey E . (1997). Am. J. Med., 102, 2–9.

  • Fischer T, Planz O, Stitz L and Rziha HJ . (2003). J. Virol., 77, 9312–9323.

  • Hall WJ, Douglas Jr RG, Hyde RW, Roth FK, Cross AS and Speers DM . (1976). Am. Rev. Respir. Dis., 113, 141–148.

  • Kerkhoff E, Fedorov LM, Siefken R, Walter AO, Papadopoulos T and Rapp UR . (2000). Cell Growth Differ., 11, 185–190.

  • Korfhagen TR, Glasser SW, Wert SE, Bruno MD, Daugherty CC, McNeish JD, Stock JL, Potter SS and Whitsett JA . (1990). Proc. Natl. Acad. Sci. USA, 87, 6122–6126.

  • Little JW, Hall WJ, Douglas Jr RG, Hyde RW and Speers DM . (1976). Ann. Intern. Med., 85, 177–182.

  • Ludwig S, Ehrhardt C, Neumeier ER, Kracht M, Rapp UR and Pleschka S . (2001). J. Biol. Chem., 276, 10990–10998.

  • Ludwig S, Engel K, Hoffmeyer A, Sithanandam G, Neufeld B, Palm D, Gaestel M and Rapp UR . (1996). Mol. Cell. Biol., 16, 6687–6697.

  • Ludwig S, Planz O, Pleschka S and Wolff T . (2003). Trends Mol. Med., 9, 46–52.

  • Marshall M . (1995). Mol. Reprod. Dev., 42, 493–499.

  • Mercer KE and Pritchard CA . (2003). Biochim. Biophys. Acta, 1653, 25–40.

  • Naumann U, Eisenmann-Tappe I and Rapp UR . (1997). Recent Results Cancer Res., 143, 237–244.

  • Ober BT, Summerfield A, Mattlinger C, Wiesmuller KH, Jung G, Pfaff E, Saalmuller A and Rziha HJ . (1998). J. Virol., 72, 4866–4873.

  • Olshaker JS . (2003). Emerg. Med. Clin. North Am., 21, 353–361.

  • Palese P, Zheng H, Engelhardt OG, Pleschka S and Garcia-Sastre A . (1996). Proc. Natl. Acad. Sci. USA, 93, 11354–11358.

  • Peschke T, Bender A, Nain M and Gemsa D . (1993). Immunobiology, 189, 340–355.

  • Pleschka S, Wolff T, Ehrhardt C, Hobom G, Planz O, Rapp UR and Ludwig S . (2001). Nat. Cell Biol., 3, 301–305.

  • Porter DD and Porter HG . (1999). Clin. Infect. Dis., 29, 437–440.

  • Ramakrishna G, Sithanandam G, Cheng RY, Fornwald LW and Smith GT . (2000). Exp. Lung Res., 26, 659–671.

  • Scholtissek C . (1997). Arch. Virol. Suppl., 13, 99–103.

  • Steinhauer DA and Skehel JJ . (2002). Annu. Rev. Genet., 36, 305–332.

  • von Gise A, Lorenz P, Wellbrock C, Hemmings B, Berberich-Siebelt F, Rapp UR and Troppmair J . (2001). Mol. Cell. Biol., 21, 2324–2336.

  • Wurzer WJ, Planz O, Ehrhardt C, Giner M, Silberzahn T, Pleschka S and Ludwig S . (2003). EMBO J., 22, 2717–2728.

Download references

Acknowledgements

We thank Katja Oesterle for great technical assistance. This work was supported in part by the Deutsche Forschungsgemeinschaft and by the EU network of excellence Virgil.

Author information

Authors and Affiliations

  1. Institut für Immunologie, Bundesforschungsanstalt für Viruskrankheiten der Tiere, Paul-Ehrlich-Str 28, Tübingen, Germany

    Veronika Ölschläger, Timo Fischer, Hanns-Joachim Rziha, Lothar Stitz & Oliver Planz

  2. Institut für Med. Virologie, FB 11, Justus-Liebig-Universität Giessen, Germany

    Stephan Pleschka

  3. Institut für Medizinische Strahlenkunde und Zellforschung (MSZ), Julius-Maximilians Universität Würzburg, Germany

    Walter Wurzer, Ulf R Rapp & Stephan Ludwig

  4. Institut für Molekulare Medizin (IMM), Heinrich-Heine Universität Düsseldorf, Germany

    Stephan Ludwig

Authors
  1. Veronika Ölschläger
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stephan Pleschka
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Timo Fischer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hanns-Joachim Rziha
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Walter Wurzer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lothar Stitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ulf R Rapp
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Stephan Ludwig
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Oliver Planz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Oliver Planz.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ölschläger, V., Pleschka, S., Fischer, T. et al. Lung-specific expression of active Raf kinase results in increased mortality of influenza A virus-infected mice. Oncogene 23, 6639–6646 (2004). https://doi.org/10.1038/sj.onc.1207883

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1207883

Keywords

This article is cited by

Search

Advanced search

Quick links