Currently circulating H5N1 avian influenza viruses are lethal to man and could cause a devastating pandemic if they became transmissible between humans. It is therefore crucial to understand the mechanisms whereby influenza virus adapts from avian to human hosts. Several recent studies have highlighted the importance for transmissibility of mutations in the proteins of the viral replicative machinery.
We propose a comprehensive study of the molecular structure and function of the influenza virus polymerase with the aim of understanding how it adapts during inter-species transmission. We will focus on determination of the atomic structure of polymerase fragments as well as the trimeric complex, which will provide the detailed framework required to understand polymerase function and the effect of specific point mutations in inter-species adaptation.
This will be coupled to /in vitro/ and /in vivo/ functional studies of the polymerase and identification of host cell interacting factors using advanced functional genomics methods. In parallel, candidate mutations that may be important for inter-species transmission and virulence will be identified by bioinformatic analysis of influenza genome sequences, updated with sequences of new H5N1 isolates, as well as from studies of laboratory strains adapted from one host to another. Functional, structural, host-factor interactome and animal infectivity studies will be performed comparatively between reference and mutated polymerase to identify mutations that are really significant in transmission and virulence.
Finally we will exploit our results by proposing a model for the evolution and host specificity of the viral replicative machinery, elaborating new molecular tools for influenza biology research and designing strategies for screening for novel anti-influenza drugs targeting polymerase. Our overall goal is to provide new knowledge that will allow us to better monitor and combat the emergence of pandemic influenza strains.
Call for proposal
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Funding SchemeSTREP - Specific Targeted Research Project