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

The 1918 Spanish Flu virus caused the worst pandemic in history infecting 30% of the globe's population and killing 30-50 million people. This virus, which was recreated at the Canadian Science Centre for Human and Animal Health (CSCHAH) based on RNA sequences obtained from tissues of victims of the 1918 pandemic, caused severe disease in mice, ferrets and non-human primates, due to aberrant immunological responses. The Spanish Flu virus serves as an excellent model to study the virulence determinants for human disease and transmission due to its avian origin, which could be useful in pandemic preparedness. Previous experiments done at CSCHAH where the HA gene from a low virulence influenza was substituted with the Spanish Flu HA gene resulted in a higher virulence virus, indicating that the Spanish Flu HA plays a major role in virulence. However, it is not fully clear which regions in the HA are involved and what are its pathogenic mechanisms since the Spanish Flu HA protein is approximately 90% similar to HA proteins from low virulence influenza viruses. Thus, identification of the regions in the Spanish Flu involved in pathogenesis could be extremely valuable for generation of targeted treatments and epidemiological monitoring of emerging avian viruses of pandemic potential. My project has two main goals: (1) identification of the residues in the Spanish Flu HA which are necessary for virulence and (2) identification of novel functions of the HA protein which could be important in pathogenesis. The first goal will be accomplished by switching specific regions between the Spanish Flu HA and an HA from a low virulence virus and then testing the lethality of viruses containing the chimeric HA's in mice and ferrets. The second goal will be accomplished by testing the viruses described previously in infectivity assays in the absence of various factors or in different cell lines, and by monitoring cellular pathways known to lead to aberrant immune responses.