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Updated: Aug 23, 2026
Modeling Dysplastic and Functional Lung Alveolar Repair after Influenza Infection
Published on: September 19, 2025
Lung-specific expression of active Raf kinase results in increased mortality of influenza A virus-infected mice
Veronika Olschläger1, Stephan Pleschka, Timo Fischer
1Institut für Immunologie, Bundesforschungsanstalt für Viruskrankheiten der Tiere, Paul-Ehrlich-Str 28, Tübingen, Germany.
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.
Insights
Activated Raf signaling in lung cells enhances influenza A virus tropism and disease severity in mice. This suggests potential for modified influenza viruses in treating Ras/Raf-driven tumors.
Area of Science:
- Molecular Biology
- Virology
- Oncology
Background:
- The Raf/MEK/ERK signaling pathway influences influenza A virus replication.
- Constitutively active Raf or MEK enhances viral propagation in cell culture.
Purpose of the Study:
- To investigate the in vivo impact of activated c-Raf (Raf-BxB) on influenza A virus propagation.
- To explore the tropism of influenza virus for cells with activated Raf signaling.
Main Methods:
- Generation of transgenic mice expressing activated c-Raf (Raf-BxB) in the lung.
- Infection of transgenic and wild-type mice with influenza A virus.
- Assessment of disease symptoms, mortality rates, viral titers, and immune response using Pseudorabies virus (PRV).
- Immunohistological analysis for influenza nucleoprotein (NP)-positive cells.
Main Results:
- Raf-BxB expression led to lung adenomas, increased disease severity, and higher mortality rates upon influenza A virus infection.
- No significant differences in influenza virus titers or immune response (PRV model) were observed between transgenic and wild-type mice.
- Immunohistology revealed increased influenza NP-positive cells in the alveolar linings of Raf-BxB mice, indicating enhanced viral tropism.
Conclusions:
- Activated Raf signaling in lung cells enhances influenza A virus tropism and exacerbates disease.
- Influenza virus shows a strong tropism for cells expressing active Raf.
- Modified influenza viruses may offer a therapeutic strategy for tumors with activated Ras/Raf signaling.
