Abwehr von Influenza- und Influenza-ähnlichen Viren durch Interferon: Bedeutung von Interferon-ß, Toll-like Rezeptoren und plasmacytoiden dendritischen Zellen
Final Report Abstract
The first goal of our research project was to use Mx1-positive mouse strains (that we had previously developed in our group) to learn about the role of various IFN types in antiviral defense of the host. This part of the project was highly successful and resulted in six publications. A second goal of the project was to identify the IFN-producing cells in virus-infected organs. This project proved to be more difficult than originally anticipated as the available antibodies failed to stain IFN-producing cells. Therefore, we switched to an alternative strategy (already mentioned in the original proposal) in which viral infection studies are performed in transgenic animals that synthesize firefly luciferase in place of IFN-ß. Such a knock-in mouse has recently been developed at the HZI in Braunschweig, and we helped characterizing this mouse. We are currently developing suitable staining techniques that will allow for the specific in situ detection of cells expressing luciferase. A third goal was to evaluate the role of Toll-like receptors (TLR) in host defense against influenza virus. During the first year of the grant period, this part of the project lost part of its attraction. First, a competing group published on this topic at an early stage of our project. They showed that MyD88-deficiency did not alter the course of the disease and that disease was less severe in influenza virus-infected TLR3-deficient animals compared to wild-type mice. Second, it became clear that the helicase RIG-I is an important cellular sensor of influenza virus. Third, our attempts to breed Mx1-positive MyD88-deficient mice were not very successful. Due to non-optimal hygienic conditions in our animal facility, these animals frequently developed various signs of disease which complicated a clean clinical evaluation of the influenza virus infection. Only recently, we could move our mice to a SPF-unit with a very high hygiene standard.
Publications
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Mx1 gene protects mice against the highly lethal human H5N1 influenza virus. Cell Cycle 6:2417-2421 (2007)
Salomon, R., Staeheli, P., Kochs, G., Yen, H.-L., Franks, J., Rehg, J.E., Webster, R.G. and E. Hoffmann
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Protective role of interferon-beta in host defense against influenza A virus. J. Virol. 81:2025-2030 (2007)
Koerner, I., Kochs, G., Kalinke, U., Weiss, U. and P. Staeheli
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The Mx1 gene protects mice against pandemic 1918 and highly lethal human H5N1 influenza viruses. J. Virol. 81:10818-10821 (2007)
Tumpey, T., Szretter, K. J., van Hoeven, N., Katz, J.M., Kochs, G., Haller, O., García-Sastre, A. and P. Staeheli
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An important role for type III interferon (IFN-l/IL-28) in toll-like receptor-induced antiviral activity. J. Immunol. 180: 2474-2485 (2008)
Ank, N., Iversen, M. B., Haugen, H., Chen, Z., Bartholdy, C., Staeheli, P., Hartmann, R., Jensen, U. B., Hansen, F. D., Thomsen, A. R., Klucher, K. & S. R. Paludan
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IFN-l is expressed in a tissue-dependent fashion and primarily acts on epithelial cells in vivo. PLoS Pathogens 4/3:e1000017 (2008)
Sommereyns, C., Paul, S., Staeheli, P., and T. Michiels
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Interferon-l contributes to innate immunity of mice against influenza A virus but not against hepatotropic viruses. PLoS Pathogens 4/9:e1000151 (2008)
Mordstein, M., Kochs, G., Dumoutier, L., Renauld, J., Paludan, S. R., Klucher, K., and P. Staeheli
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Novel reporter mouse reveals constitutive and inflammatory expression of IFN-ß in vivo. J. Immunol. 183: 3229-3236 (2009)
Lienenklaus, S., Cornitescu, M., Zietara, N., Lyszkiewicz, M., Gekara, N., Jablonska, J., Edenhofer, F., Rajewsky, K., Bruder, D., Hafner, M., Staeheli, P., and S. Weiss
