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FLUINNATE


Biology, Target Search and Drug Discovery

Innate Immunity in Influenza Virus Infection of Mammalian Airways

EC contribution
: € 1 436 130
Duration
: 36 months
Starting date
: 01/01/2007
Instrument
: STREP
Keywords
: Emergent diseases, emerging influenza A virus, viral pathogenicity factors, interferon, innate immunity, human airway epithelium, host range, antiviral response
Project Number
: SP5B-CT-2006-044161
Web-site
: www.fluinnate.org

Summary:

Emerging influenza A virus (FLUAV) infections pose a considerable health threat to mankind. The molecular determinants governing increased virulence of emerging virus strains in humans are presently not well understood. FLUINNATE proposes to identify and study the essential viral and host factors that determine the outcome of infection. FLUAV enters the human respiratory tract and must replicate in the face of multiple innate immune defence mechanisms to establish infection in vivo.

Successful viruses must adapt to intrinsic cellular restriction factors and evolve the capacity of circumventing the antiviral interferon (IFN) response, either by limiting IFN production or by blocking IFN actions. We will test the hypothesis that the speed and efficiency by which a given virus circumvents these early host responses are critical determinants in its host range and pathogenicity. In this respect, the crucial role of the virus polymerase and its cellular interactors will be analysed. Likewise, the importance of the IFN-inducible Mx GTPase as a major anti-FLUAV effector molecule will be evaluated.

Virus-induced inflammatory cytokines and chemokines exert powerful effects against FLUAV in lung epithelial cells. However, they may be detrimental to the host, causing accelerated influenza pathogenesis in the human respiratory tract. We will analyse viral factors governing the innate antiviral cytokine response and determine the impact of these factors on virus growth, cell survival and pathogenicity. Human, avian and porcine FLUAV will be used in animal models and in cell culture systems, such as human airway epithelium. The present studies should generate important information that will help to better understand the processes involved in the emergence of lethal influenza viruses and to develop efficient control measures against these devastating pathogens.

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