The Role of Phosphoinositides in Influenza Virus Assembly - Influenza virus causes significant illness and mortality in the U.S. and worldwide. Vaccines offer
some protection, but must be continuously tailored to 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 urgently needed. The viral surface
glycoprotein hemagglutinin 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. Assembly depends on hemagglutinin co-clustering with other viral
components, including the matrix protein M1, in the host cell plasma membrane. This project will
address the fundamental questions of how hemagglutinin forms clusters, how hemagglutinin
and M1 co-cluster, and the role of host cell components in these key viral processes. We
recently discovered that hemagglutinin and M1 both interact with host cell phosphoinositides,
which are able to control important cell signaling and protein trafficking pathways that have been
implicated previously in infection. This project will investigate the mechanism of interaction
between hemagglutinin, M1, and the phosphoinositides PI4P and PIP2 using super-resolution
microscopy, fluorescence spectroscopy, and molecular dynamics simulations, 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 exploit
host cell membrane organization for its own life cycle.
