Institute of Virology

In collaboration with:

• Dr. M. Matrosovich, Institute of Virology, University of Marburg, Germany: Characterization of the viral glycoproteins.
• Dr. A. Garcia-Sastre, Mount Sinai School of Medicine, Department of Microbiology, New York, USA: Virulence factors of influenza A viruses.
• Dr. P. Stäheli, Institute of Virology, Freiburg: Virulence of mouse-adapted influenza viruses in Mx1-mice.

Abstract:

Virulence and pathogenesis of influenza A viruses is mostly determined by the viral glycoproteins, the activity of the viral polymerase complex and the viral non-structural proteins PB1-F2 and NS1. Using mouse-adapted isolates of A/PR/8/34 (H1N1) and A/HK/01/68 (H3N2) we characterize Influenza A virus strains with unexpected high virulence for Mx1-positive mice. The basis of this high virulence is an extremely fast virus multiplication in the infected lung that out competes the interferon-induced antiviral response of the host. In our current project we analyse the role of the viral NS1 protein to allow the virus escape from the interferon-induced host defence. Without NS1-mediated control, viral infection leads to the production of interferons that subsequently induce interferon-stimulated gene products with antiviral activity. This is best shown in Mx1-positive mice, carrying intact alleles of the interferon-induced Myxovirus resistance gene Mx1. Using reverse genetics we manipulate influenza viruses in order to analyze the contribution of functional domains of NS1 for suppression of the antiviral host defense. The goal of these studies is to understand the role of the multi-functional NS1 protein on virulence and pathogenesis of highly virulent influenza viruses.

Selected References:

• Lohrmann, F., Dijkman, R., Stertz, S., Thiel, V., Haller, O., Staeheli, P., and and Kochs, G.
  Emergence of a C-terminal seven amino acid elongation of NS1 around 1950 conferred a minor growth advantage to former seasonal influenza A viruses.
  JVI 87: 1271-13 (2013)
• Koerner, I., Matrosovich, MN., Haller, O., Staeheli, P., Kochs, G.
  Altered receptor specificity and fusion activity of the haemagglutinin contribute to high virulence of a mouse-adapted influenza A virus
  J Gen Virol 93: 970-979 (2012)
• Steidle, S., Martínez-Sobrido, L., Mordstein, M., Lienenklaus, S., García-Sastre, A., Staeheli, P. and Kochs, G.
  Glycine 184 in the non-structural protein NS1 determines virulence of influenza A virus strain PR8 without affecting the host interferon response
  JVI 84: 12761-12770 (2010)
• Kochs, G., Martínez-Sobrido, L., Lienenklaus, S., Weiss, S., García-Sastre, A., and Staeheli, P.
  Strong interferon-inducing capacity of a highly virulent variant of influenza A virus strain PR8 with deletions in the NS1 gene
  J Gen Virol 90: 2990-2994 (2009)
• Rolling, T., Koerner, I., Zimmermann, P., Holz, K., Haller, O., Staeheli, P., and Kochs, G.
  Adaptive Mutations Resulting in Enhanced Polymerase Activity Contribute to High Virulence of Influenza A Virus in Mice
  J Virol 83: 6673-6680 (2009)
• Grimm, D., Staeheli, P., Hufbauer, M., Koerner, I., Martínez-Sobrido, L., Solórzano, A., García-Sastre, A., Haller, O., Kochs, G.
  Adaptive mutations resulting in enhanced polymerase activitiy contribute to high virulence of influenza A virus in mice
  JVI 83: 6673-6680 (2009)
• Kochs, G., García-Stastre, A., Martínez-Sobrido, L.
  Multiple anti-interferon actions of the influenza A virus NS1 protein.
  J Virol 81: 7011-7021 (2007)