Structural Studies of Influenza Virus Restriction Factors

Influenza viruses cause seasonal epidemics and occasional pandemics which pose a significant burden to public health and the global economy. Influenza viruses are segmented, negative-sense RNA viruses, meaning that each infectious viral particle must contain eight viral ribonucleoprotein (vRNP) complexes - containing viral RNA wrapped around nucleoprotein monomers bound to the influenza polymerase complex. This core unit is responsible for efficient genomic packaging and viral replication. Various human proteins (host factors) are required for viral replication, or else are key in the host antiviral immune response. However, detailed mechanistic and structural insights are lacking. Of particular interest is the interaction between vRNPs and Human Myxovirus Resistance Protein 1 (MxA) - a host factor known to restrict the replication of certain influenza virus strains. Primarily using specialised electron microscopy techniques, I will examine: - The structural basis of MxA-mediated restriction of influenza virus in the innate host immune response - How key mutations in certain strains of influenza can lead to humans becoming more susceptible to infection Improved understanding of the influenza lifecycle and of the involvement of host factors in the immune response will be useful to inform future structure-based drug design in the pursuit of specific inhibitors of influenza virus replication.