WP1 - Molecular basis of high influenza virus virulence in mice with a functional Mx1 resistance gene

Partners involved:
N° 1, Prof. Otto Haller (WP Leader)
N° 5, Dr. Ervin Fodor
N° 6, Dr. Nadia Naffakh

The aim of WP1 is to identify the critical virulence factors which allow influenza A virus growth in fully immunocompetent hosts. The emphasis will be on viral and host factors that determine the very early steps of infection. Previous work in mice has been hampered by the fact that the classical inbred mouse strains have a defective innate immune response against influenza viruses, because they lack a functional Mx1 gene. The IFN-inducible MxGTPase is the major effector molecule blocking FLUAV replication in infected cells. We will account for this by using mice with the wild-type Mx1 gene and by using an exceptional influenza A virus strain which is highly pathogenic in mice. We will identify the genes and gene products of this virus that determine its unusual properties. Preliminary evidence indicates that one of the factors responsible for high virulence is the viral polymerase complex. We propose to analyze the polymerase subunits and to determine their individual contributions to polymerase activity. We will establish the role of the polymerase complex and additional viral factors in virus escape from the early host innate defense mechanisms. It is likely that specific interactions with host cell factors modulate the viral polymerase activity and we will try to identify such cellular interactors. The results will generate useful knowledge about super-active polymerase genes that can be utilized to increase yields of recombinant (vaccine) viruses by reverse genetics. They will further yield basic knowledge regarding the molecular mechanisms of extraordinary virus virulence.