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

病毒感染的第一步是进入易感细胞。这几乎总是涉及病毒表面的蛋白质和细胞之间的相互作用，对于被脂质包膜包围的病毒，随后病毒和宿主细胞膜融合。病毒生命周期的这一步是病毒从其自然宿主跳到另一个物种时遇到的第一个障碍。我们最近的研究表明，埃博拉病毒迅速进化，变得更适合进入人类细胞，但其背后的机制仍有待阐明。尽管病毒表面蛋白的宿主蛋白（受体）结合区及其周围的关键突变位置表明，受体结合是一个关键的决定因素，但越来越多的证据表明，其他步骤，例如融合，可能受到病毒进化的影响。在这个项目中，我们将开发一种转基因小鼠，并利用一系列体外试验来研究埃博拉病毒和马尔堡病毒的传染性，并确定在病毒和不同宿主中观察到的遗传变异如何影响这一过程。这些发现将帮助我们更好地了解病毒溢出事件，使我们能够确定可能导致人畜共患风险增加和随后的人类传播性增加的遗传特征，并确定从本质上更容易受到疫情加剧风险的人群。这些发现将有助于改善未来的疫情监测和应对，并为开发改进的疫苗和疗法提供信息。

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.