Understanding the fundamental mechanisms of viral activation in the host

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Although much research has been done on the influenza virus over the years, strikingly very little is known about the way the influenza fusion protein hemagglutinin is processed by host enzymes for it to become infectious. Furthermore, only recently have some of the host influenza activating enzymes been identified. We have identified one such enzyme in the cells lining the respiratory tract of humans. To date the current dogma on influenza hemagglutinin activation by host enzymes is that the amino acid sequence present at the cleavage site dictates the type of enzyme that will carry out the activation of the fusion protein. Based on the literature and on our most recent discoveries, we believe that this view of hemagglutinin activation is overly simplistic and that there exist other crucial determinants of viral hemagglutinin and host enzyme interaction, which lead to the protein's processing and activation. In this proposal we aim to elucidate the forces that govern this interaction process and the structural features of influenza hemagglutinin that influence and that are critical for the interaction to take place. To do so, we will use sophisticated and cutting-edge biochemical, biophysical and molecular techniques to study the interaction of H1 and H3 subtype viruses with two influenza-activating enzymes of the host, one that has been identified a few years ago and one that we have newly identified recently. Thus the long-term goal of this research program is to understand the fundamental forces, structural determinants and mechanisms of the interaction of viral fusion proteins with host enzymes, which lead to their activation. This research program should have a significant impact on the field of virology by providing fundamental information on how viral proteins interact with enzymes that activate them in the host. It should also provide vital information to researchers in both academic settings and in the biotech/pharmaceutical sectors who are interested in developing novel influenza antivirals. Canadians will benefit from this research economically through the generation of novel Canadian intellectual property, and in public health through the future development of new antiviral therapies.