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Host-Specific variants of the influenza virus replication machinery

Objective

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

FP6-2005-SSP-5-B-INFLUENZA
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Funding Scheme

STREP - Specific Targeted Research Project

Coordinator

EUROPEAN MOLECULAR BIOLOGY LABORATORY
Address
Meyerhofstrasse 1
Heidelberg
Germany

Participants (6)

UNIVERSITE JOSEPH FOURIER GRENOBLE 1
France
Address
621 Avenue Centrale Domaine Universitaire
Grenoble
INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
France
Address
101 Rue De Tolbiac
Paris
CONSEJO SUPERIOR DE INVESTIGASIONES CIENTIFICAS
Spain
Address
Serrano, 117
Madrid
PHILIPPS - UNIVERSITAET MARBURG
Germany
Address
Biegenstrasse 10
Marburg
MEDICAL RESEARCH COUNCIL
United Kingdom
Address
20 Park Crescent
London
FRIEDRICH LOEFFLER INSTITUTE
Germany
Address
Suedufer 10
Greifswald - Insel Riems