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Institute of Virology

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MxGTPase: Mediator of influenza virus resistance in mice

Mice are frequently used as an animal model to study the pathogenesis of influenza A viruses However, standard laboratory mice do not possess a complete antiviral defense system, as they carry defective alleles of the Mx1 gene. Consequently, mice carrying a wild-type Mx1 gene (Mx1+/+) differ from standard laboratory mice (Mx1−/−) in being highly resistant to infection with influenza A virus. The Mx1 gene is under tight transcriptional control of alpha/beta interferon (IFN-α/β) and codes for a nuclear 72-kDa protein which represents a decisive antiviral factor that controls influenza virus infections in mice.

Health status of mice expressing (Mx1+/+) or lacking (Mx1-/-) functional alleles of the influenza virus resistance gene Mx1 at 4 days post infection with influenza A virus.

Open questions presently being investigated include:
a) Structural and functional analysis of Mx genes from wild mice
b) Viral resistance of transgenic mice expressing Mx gene of human origin

Selected Publications from our group

  1. Grimm D, Staeheli P, Hufbauer M, Koerner I, Martínez-Sobrido L, Solórzano A, García-Sastre A, Haller O, Kochs G. Replication fitness determines high virulence of influenza A virus in mice carrying functional Mx1 resistance gene. Proc. Natl. Acad. Sci. USA 104: 6806-6811 (2007).
  2. Tumpey T, Szretter KJ, van Hoeven N, Katz JM, Kochs G, Haller O, García-Sastre A, Staeheli P. The Mx1 gene protects mice against pandemic 1918 and highly lethal human H5N1 influenza viruses. J. Virol. 81: 10818-10821 (2007)
  3. Rolling, T., Koerner, I., Zimmermann, P., Holz, K., Haller, O., Staeheli, P. & G. Kochs. Adaptive mutations resulting in enhanced polymerase activity contribute to high virulence of influenza A virus in mice. J. Virol. 83: 6673-6680 (2009)
  4. Xiao, H., Killip, M.J., Staeheli, P., Randall, R.E., & D. Jackson. The human interferon-induced MxA protein inhibits early stages of influenza A virus infection by retaining the incoming viral genome in the cytoplasm. J. Virol. 87: 13053-13058 (2013)
  5. Verhelst, J., Spitaels, J., Nürnberger, C., De Vlieger, D., Ysenbaert, T., Staeheli, P., Fiers, W., & X. Saelens. Functional comparison of Mx1 from two different mouse species reveals the involvement of loop L4 in the antiviral activity against influenza A viruses. J. Virol. 89: 10879-10890 (2015)
  6. Pillai, P.S., Molony, R.D., Dong, H., Pang, I.K., Tal, M.C., Mohanty, S., Homer, R.J., Montgomery, R.R., Shaw, A.C., Staeheli, P., & A. Iwasaki. Mx1 reveals innate pathways to antiviral resistance and lethal influenza disease. Science 352: 463-466 (2016)
  7. Nürnberger, C., Zimmermann, V., Gerhardt, M., & P. Staeheli. Influenza virus susceptibility of wild-derived CAST/EiJ mice results from two amino acid changes in the MX1 restriction factor. J. Virol. 90: 10682-10692 (2016)
  8. Deeg, C.M., Hassan, E., Mutz, P., Rheinemann, L., Götz, V., Magar, L., Schilling, M., Kallfass, K., Nürnberger, C., Soubies, S., Kochs, G., Haller, O., Schwemmle M., & P. Staeheli. In vivo evasion of MxA by avian influenza viruses requires human signature in the viral nucleoprotein. J. Exp. Medicine 214: 1239-1248 (2017)

Collaboration

  • Prof. Georg Kochs, Institute of Virology, University Medical Center Freiburg
  • Prof. Martin Schwemmle, Institute of Virology, University Medical Center Freiburg