EUROFLU

EC contribution

: € 1 355 811

Duration

: 36 months

Starting date

: 01/01/2007

Instrument

: STREP

Keywords

: Avian influenza viruses, pathogenicity, transmission, replication, virulence, vaccines, drugs, diagnosis

Project Number

: SP5B-CT-2007-044098

Web-site

: -

Problem:

Influenza is currently considered one of the most severe threats to human health and animal welfare. During the past 10 years outbreaks of HPAIV have occurred mostly in Central and East Asia, and since 1999 these viruses have also been found in the Middle East as well as in Eastern and Southern Europe. The unprecedented spread of the H5N1-type HPAIV in poultry and wild waterfowl throughout Asia, Europe and more recently in West Africa, has been associated with at least 241 transmissions to humans with a case fatality rate (CFR) of more than 50%. The virus also spread to several other mammalian species including cats. Should these viruses acquire the capacity for easy human-to-human transmission, the outbreak of a new influenza pandemic with a considerably high CFR could be expected.

Several infections of humans with the recent HPAIV H5N1 viruses have been characterised by an unusually strong cytokine response in the host ('cytokine storm') that appears to contribute to viral pathogenicity. There are also first indications of a neuro- and an endothelial-tropism of recent HPAIV in mammals. The molecular basis of the latter findings that may determine virulence and host cell tropism is not known and needs to be urgently defined.

To date there is no vaccine against H5N1 and variants resistant to current antiviral drugs are emerging. This highlights the urgent need for fast and specific diagnosis, an effective vaccine and new efficient antiviral drugs.

Aim:

The overall objective of the EUROFLU consortium is to understand the molecular determinants and the mechanisms responsible for virulence, host specificity, inter-species transmission and pathogenicity of HPAIV, which will eventually accelerate the development of effective diagnostic tools, anti-HPAIV vaccines and drugs.

To achieve this goal an interdisciplinary consortium of experts in virology, immunology and bio-computing has been established. EUROFLU will provide European authorities, policy makers and the community with advanced scientific knowledge supporting a successful control of avian influenza. The specific research aims are:

1. Defining virus/cell surface-interactions:
   This section of the scientific work aims to characterise the specific interaction between domains of the haemagglutinin subunit 1 (HA1) and the host-cell receptor (termed as recognition and targeting markers (RTMs)) as one of the main factors determining host range. This task will be approached by advanced computational and biochemical analysis. Focus will be on human and avian isolates of the H5 and H7 types of HPAIV and results will be compared with data gained from human H1 and H3 virus strains including the 1918 'Spanish Flu'.
2. Analysing intra-cellular virus/host-interactions:
   This part of the projects aims to understand the molecular mechanisms of interaction between HPAIV and host-cell factors and the role of these interactions for viral pathogenesis. The analyses will involve reverse genetics, genomic and proteomic techniques and will elucidate the similarities and differences of how HPAIVs replicate in avian and mammalian host cells and how they evade cellular defences. Furthermore, the current knowledge on HPAIV's misuse of cellular activities to support their propagation will be extended.
3. Determining virus/host-interactions in animal hosts. The studies in this section of the project will use mouse and chicken model systems for: (i) the characterisation of immune responses after HPAIV infection (ii) the investigation of mechanisms of viral neurotropism and neuropathogenicity in mammals and in birds.

Expected results:

1. VIRUS/CELL SURFACE INTERACTIONS:
   The expected outcome is enhanced knowledge of HPAIV cell specificity and tropism by the identification and characterisation of RTMs and through the investigation of HPAIV-RTM/host cell receptor interaction. This will lead to the identification of viral and cellular structures that can be used for diagnosis and for the generation of new vaccines and might be interesting targets for drugs designed to block virus/cell interaction.
2. INTRA-CELLULAR VIRUS/HOST INTERACTIONS:
   This analysis is expected to increase the understanding of: (i) HPAIV replication in avian and in mammalian host cells; (ii) the viral mechanisms aimed at evading cellular defences; (iii) the HPAIV usage of cellular mechanisms for their propagation.
   
   The knowledge gained will allow the characterisation of viral conditions that define cell tropism (avian or human) of HPAIV and will also pave the way for new anti-HPAIV drugs interfering with virus replication.
3. VIRUS/HOST INTERACTIONS IN ANIMAL HOSTS:
   The results of this analysis will elucidate basic virulence mechanism(s) in the studied mouse and chicken models and they will also give important insights into the course of H5N1 infections in humans, which will help to adjust the medical treatment of patients.

Potential applications:

Results gained in the EUROFLU project will provide the knowledge base for new therapeutic approaches in the development of improved diagnostic tools and of vaccines to block HPAIV infections. It will set the molecular basis for new anti-viral drugs against influenza viruses independent of the specific virus strain and circumvent the constant risk of selecting resistant viral variants that make current drugs ineffective. The new understanding of virulence mechanisms will help to develop new strategies for the treatment of patients.

The EUROFLU STREP is composed of four Work Packages (WP1-4) and four Scientific Teams (Computational, Virology, Biochemical and Model Organism). The management in WP4 is headed by the Coordinator who will be assisted by the Administrative Manager and a Management Board, which includes members of the consortium. Each WP is headed by a Work Package Leader (WPL), who will implement the scientific and organisational decisions of the management. The scientific teams will work on the indicated topics and will strongly interact within the consortium.

Coordinator:

Partners: