Grant: Doctoral Award - Frederick Banting and Charles Best Canada Graduate Scholarships

Annually, influenza A virus epidemics are a leading cause of disease and mortality in industrialized countries. Sporadically, pandemic strains can be globally devastating, as it was for the 1918 influenza outbreak killing 20-50 million people. The unexpected spread of the H1N1 "swine flu" strain in the past months demonstrates the difficulty of predicting and preventing the outbreak of a pandemic flu strain. One way to overcome this is to focus on disease mechanisms shared by many highly pathogenic (hp)-flu strains. Clinical reports and animal models of hp-flu infection (H5N1 avian and 1918 pandemic flu) have identified overwhelming host responses as a key factor of severe disease. This knowledge may lead to common, rather than strain-specific, therapies against hp-flu. Experimental infection of mice has proven useful in discovering new pathways of host defence against pathogens. We have produced a mouse model of hp-flu in which the susceptible A/J strain presents the hallmark of an overwhelming host response, whereas the resistant C57BL/6 strain overcomes infection. In genetic analysis of specialized mice (recombinant congenic strains) issued from A/J and C57BL/6 progenitors, we identified a mouse genome locus, Myxovirus resistance 3 (Mx3) that is strongly associated with mild response and resistance to influenza infection. Compared to conventional strategies, our approach should accelerate the identification of functional pathways key to the influenza response because 1- we already have the Mx3 segment isolated in a recombinant congenic strain; 2- we will use immunologic, cell biology, and bioinformatic methods to compliment traditionally time intensive forward genetics approaches to gene identification. Investigation of Mx3 should improve our understanding and control of aberrant host responses against influenza infection; this represents a window of opportunity to dampen disease severity and reduce the toll of future pandemic outbreaks of hp-flu strains.