Assessing the impact of host and virus genetic variability on Filovirus cell entry and infectivity

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The first step in virus infection is entry into a susceptible cell. This almost always involves interaction between proteins at the surface of the virus and the cell and, for viruses surrounded by a lipid envelope, subsequent fusion of the virus and host cell membranes. This step of the virus life cycle is the first barrier encountered when a virus jumps from its natural host into another species. We have recently shown that Ebolavirus rapidly evolves to become better adapted for human cell entry but the mechanism underlying this remains to be elucidated. Although the location of key mutations in and around the host protein (receptor) -binding region of the virus surface protein suggest that receptor binding is a key determinant there is increasing evidence to suggest that other steps, for example fusion, may be affected by virus evolution. In this project we will develop a genetically modified mouse, and utilise a range of in vitro assays to study the infectivity of Ebola and Marburg viruses and define how genetic variation observed in both virus and different hosts affects this process. These findings will help us understand better virus spillover events and enable us to identify genetic signatures that may lead to increased zoonotic risk and subsequent human transmissibility as well as identify human populations that are inherently more at risk from heightened outbreaks. Together these findings will lead to improved future outbreak monitoring and response and also inform development of improved vaccines and therapies.