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Molecular basis of high virulence of influenza viruses in mice
(Project jointed directed by Georg Kochs, Otto Haller and Peter Staeheli)
Students currently involved in project: Iris Körner, Petra Zimmermann, Thierry Rolling
Funding: European Community (FLUINNATE) and Deutsche Forschungsgemeinschaft (DFG)
The interferon (IFN)-induced resistance factor Mx1 is a critical component of innate immunity against influenza A viruses (FLUAV) in mice. Animals carrying a wild-type Mx1 gene (Mx1+/+) differ from regular laboratory mice (Mx1-/-) in being highly resistant to infection with standard FLUAV strains. We identified an extraordinary variant of the FLUAV strain A/PR/8/34 (H1N1) (designated hvPR8) which is unusually virulent in Mx1+/+ mice. hvPR8 was well controlled in Mx1+/+ but not Mx1-/- mice provided the animals were treated with IFN before infection, indicating that hvPR8 exhibits normal sensitivity to growth restriction by Mx1. hvPR8 multiplied much faster than standard PR8 early in infection due to highly efficient viral gene expression in infected cells. Studies with reassortant viruses containing defined genome segments of both hvPR8 and standard PR8 demonstrated that the HA, NA and polymerase genes of hvPR8 all contributed to virulence, indicating that efficient host cell entry and early gene expression renders hvPR8 highly pathogenic. These results reveal a surprisingly simple concept of how influenza viruses may gain virulence and illustrate that high speed of virus growth can outcompete the antiviral response of the infected host.
We found that viruses containing the HA of hvPR8 are less sensitive to ammonium chloride-mediated increase of the intracellular pH during virus entry into cells and accordingly fuse with target membranes at higher pH compared to viruses containing the HA of standard PR8 (lvPR8). hvPR8 showed substantial binding to 2,6-linked sialic acids, whereas lvPR8 did not. Both virus strains bound 2,3-linked sialic acids, but lvPR8 exhibited higher affinity for this receptor. To address the importance of these features for virulence, we are presently generating viruses with single or multiple amino acid exchanges in HA.
Recently we also started analyzing this highly virulent PR8 virus by combining its polymerase subunits with those of its low virulent counterpart. We found that PB2 and to a lesser extent PA contribute to high replication efficiency as shown in a minireplicon system and to high virulence as shown by infecting Mx1+/+ mice with reassortant viruses. To identify critical amino acids that contribute to the high virulence phenotype, single amino acid exchanges in PB2 and PA are evaluated at present.
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Health status of animals and appearance of lungs of Mx1+/+ mice at day 4 post intranasal infection with either 1,000 plague-forming units of either lvPR8 (left) or hvPR8 (right). |
Selected Publications
- Grimm, D., Staeheli, P., Hufbauer, M., Martínez-Sobrido, L., Solórzano, A., García-Sastre, A., Haller, O. & G. Kochs. 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).
Current collaborators in this project:
- Prof. Mikhail Matrosovich (Institute of Virology, University of Marburg, Germany)
- Dr. Ervin Fodor (Institute of Pathology, University of Oxford, UK)
- Prof. A. Garcia-Sastre (Mount Sinai School of Medicine, New York, USA)
