The Language of Zoonosis: Rationalising Receptor-Mediated Spillover of Viral Pathogens at a Molecular Level

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Despite global advances in virus detection and surveillance, we lack the capability to predict which viruses can cross the species barrier and cause disease. This process is dependent on a number of factors: most importantly, the ability of a virus to target specific cell types by binding to receptors displayed on the host-cell surface. Using a multidisciplinary structural and molecular biology approach, I will define the rules of virus-host receptor engagement for emergent paramyxoviruses and elucidate the molecular mechanism by which paramyxoviruses viruses undergo attachment and fusion with host cells. This will be addressed in the context of both intact virus and the individual structural glycoproteins responsible for viral entry. This investigation will include a focus on animal morbilliviruses, a group of pathogens for which there is a paucity of molecular understanding of host cell entry processes. Principal goals of this work will be to elucidate the mechanism of receptor-mediated entry of paramyxoviruses into a host cell and to reveal viral envelope determinants of cross-species transmission, at a molecular level. This will involve the combination of high-resolution structural studies on isolated molecules with lower resolution analyses of intact viral prototypes. This work will both enhance our understanding of paramyxovirus pathobiology and also allow prediction of the zoonotic risks associated with newly reported viruses. The information derived from these combined techniques will ultimately aid in our ability to combat these pathogens.There are four complementary goals:1. Recombinant expression and purification of paramyxoviral attachment glycoproteins and cognate receptors, preparation of virus-like particles, and the acquisition/development of neutralising antibodies (nAbs) against these glycoproteins.2. Crystallographic analysis of paramyxoviral glycoproteins alone and in complex with cellular receptors and nAbs to provide atomic descriptions in pre- and post-fusion assemblies, and to illustrate the morphological changes required for viral entry.3. Cryo-electron microscopy analysis of intact, non-pathogenic viral orthologues to visualise the ultrastructure of these viruses, the assembly of their subunit glycoproteins, and to provide a structural basis for receptor and antibody interactions for entire virions.4. To complement structure-predicted determinants for virus host cell entry with in vitro functional analyses.