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Influenza A virus: Mechanisms of Enhanced Virulence

Investigators:

Valentina Wagner	Petra Zimmermann	Florens Lohrmann
Peter Staeheli	Otto Haller	Georg Kochs

In collaboration with:

• Prof. M. Matrosovich, Institute of Virology, University of Marburg, Germany: Characterization of the viral glycoproteins.
• Dr. Ervin Fodor, Institute of Pathology, University of Oxford, GB: Characterization of the viral polymerase complex.
• Prof. A. Garcia-Sastre, Mount Sinai School of Medicine, Department of Microbiology, New York, USA: Virulence factors of influenza A viruses.

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) we characterized an Influenza A virus strain 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 outcompetes the interferon-induced antiviral response of the infected host. Analysis of reassortant viruses demonstrated a multifactorial basis of this enhanced virulence including the hemagglutinin, the viral polymerase complex as well as the viral interferon antagonist NS1. In our current research we analyse the contribution of the single viral components and the molecular mechanisms that determine this speed up of virus multiplication and thereby escape from the interferon-induced host defence.

Selected References:

• 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.
  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)
• 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)

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