The Evolution of Ebolavirus its Interaction with the Host Cell Receptor, NPC1

There are five known species of Ebolavirus, with Zaire Ebola Virus (EBOV), acting as etiological agent of the infamous Ebola Virus Disease. The last major outbreak occurred in West Africa, between 2013 and 2016 and was unprecedented both in terms of its geographical scale and its duration. Those unfortunate enough to contract the deadly disease experience fever, systemic inflammation and damage to their endothelial cell lining. These symptoms rapidly advance to internal haemorrhaging, shock and multiorgan failure, leading to observed mortality rates of up to 90%. Outbreaks often have a zoonotic origin and are then sustained via human to human transmission through contact with bodily fluids of infectious individuals or the deceased. However, ambiguity still exists regarding the virus' animal reservoir, although fruit bats are the primary suspect implicated in the transmission of virus to hosts susceptible to disease. Ebolavirus is a threat to global public threat, particularly in areas often lacking the appropriate infrastructure to support the containment of the disease and provide the best responses in disease management. Therefore, a continued understanding of the virus, its interactions and how it may evolve, is needed at a molecular level to aid in infection control, drug development and other therapeutic options. Continued probing into the complex nature of the interaction between the virus and its host cell receptor, NPC1, will be paramount in this.


The main aim of this project is to be able to determine any naturally occurring polymorphisms that exist within human NPC1, amongst populations across different geographic areas, and the impact that these may have on the susceptibility of these hosts, to EBOV infection.

This will hopefully enable the identification of genetic signatures that some populations may intrinsically possess, leading to an increased risk to zoonosis and any subsequent human transmission events. This will lead to the recognition of populations that may be more at risk to infection during a large outbreak, or experience increase disease severity. Consequently, public health policies can be informed in order to improve outbreak management and responses in the future. It is hypothesised that since the outbreaks are traditionally restricted to Africa, that people of an African decent may display some mutations at different frequencies than other populations, which may be more inherently resistant and thus be more vulnerable to infection.

Additionally, efforts will also be made to try and determine NPC1 polymorphisms that impact EBOV entry cross other hosts, in particular primate and bat species. This will help define species determinants that shape EBOV entry, thus providing an improved understanding of spill-over events in the wild, which have been shown to directly correlate with human outbreaks in the past.

Since viral evolution can significantly impact on epidemic spread and disease severity, in addition to other factors such as the environment and public health, the final aim of the project will be to establish the impact that the long-term evolution of EBOV has had on both its infectivity and tropism. This will be completed by characterising ancestral node sequences that have been synthesised and comparing their infectivity against extant sequences that are representative of all EBOV outbreaks that have occurred since 1976, in different cell lines, including human and bat. This will be an important measure of the rapidity of EBOV evolution in outbreaks where extensive sampling was not completed. It will also inform the development of future therapeutics in ensuring that they are effective against all major strain variants that have caused past outbreaks as well as provide more evidence that fruit bats are the reservoir species.