Mechanism of Interaction between Influenza Hemagglutinin and Host Cell Phosphoinositides

Influenza virus causes significant illness and mortality in the U.S. and worldwide. Vaccines offer some protection, but must be continuously tailored to seasonal mutations of the virus. Some strains of influenza are resistant to one or more of the limited number of available anti-viral drugs. New strategies which attack invariant features of the virus are desperately needed. The protein hemagglutinin, found on the surface of the virus, allows the virus to bind to host cells and enter. Entry depends on high density clusters of hemagglutinin within the viral membrane, but the mechanism of cluster formation is unknown. This project will address the fundamental question of how hemagglutinin forms clusters, even in the absence of other viral components, by hijacking cellular components. We recently discovered that hemagglutinin interacts with a particular host cell lipid (PIP2) that is able to control the host cell cytoskeleton and several signaling pathways that have been implicated previously in infection. This project will investigate the mechanism of interaction between hemagglutinin and PIP2 using super- resolution microscopy and other fluorescence methods, targeting the portions of hemagglutinin that are invariant and therefore less likely to mutate over time. Results will help identify new targets for anti-viral drugs and illuminate how influenza is able to modify the host cell cytoskeleton and plasma membrane for its own life cycle.