Engineering and targeting glycan receptor binding of influenza A virus hemagglutinin

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biological Engineering, 2011.Cataloged from PDF version of thesis.Includes bibliographical references (p. 217-232).The critical first step in the host infection by influenza A virus is the binding of the viral surface glycoprotein hemagglutinin (HA) to the sialylated glycan receptors terminated by N-acetyineuraminic acid (Neu5Ac) expressed on the host cell surface. Glycans terminating in Neu5Ac that is a2-6 and a2-3 linked to the penultimate galactose serve as receptors for human- and avian- adapted influenza A virus respectively. This thesis focuses on studying HA, glycan receptors and their interactions both in a biochemical and physiological context to understand the role of these interactions in influenza A virus pathogenesis. The first Specific Aim of this thesis deals with understanding the molecular determinants of glycan receptor-binding specificity and affinity of HA (or avidity in the context of the whole virus) and how these properties govern antigenic drift and efficiency of airborne transmission. This approach contributed to uncovering the relationship between receptor-binding affinity and efficiency of transmission of the 2009 H1N1 pandemic influenza A virus and also predicting the evolution of this virus into a more transmissible strain. The second Specific Aim of this thesis focuses on understanding the distribution of the glycan receptors for human-adapted HA (going beyond a2-3/aX2-6 linkages), in ferret (animal model for influenza research) and in human respiratory tracts. Based on this understanding, this part of the thesis contributed to developing new anti-viral strategies based on targeting the host glycan receptors (instead of the common strategies that directly target the viral proteins) Overall, this thesis has provided functional insights into the role of HA-glycan interaction in viral pathogenesis. As part of this research, various tools and methods were developed. Further, such an approach paves way for elucidating the functional significance of important protein-glycan interactions in other disease models.by Akila Jayaraman.Ph.D