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

已知的埃博拉病毒有五种，其中扎伊尔埃博拉病毒(EBOV)是臭名昭著的埃博拉病毒病的病原体。上一次重大疫情发生在西非，发生在2013至2016年间，无论从地理规模还是持续时间来看，都是史无前例的。那些不幸感染这种致命疾病的人会出现发烧、全身炎症和内皮细胞衬里受损的症状。这些症状迅速发展为内出血、休克和多器官衰竭，导致观察到的死亡率高达90%。暴发通常源于人畜共患病，然后通过接触感染者或死者的体液，通过人与人之间的传播得以持续。然而，关于病毒的动物宿主仍然存在歧义，尽管果蝠是将病毒传播给易感疾病的宿主的主要嫌疑人。埃博拉病毒是对全球公共威胁的威胁，特别是在往往缺乏适当基础设施来支持控制疾病和在疾病管理中提供最佳应对措施的地区。因此，需要在分子水平上继续了解病毒、其相互作用以及它可能如何演变，以帮助控制感染、药物开发和其他治疗选择。继续探索病毒与其宿主细胞受体NPC1之间相互作用的复杂性质，将是至关重要的。这个项目的主要目的是能够确定人类NPC1中存在的任何自然发生的多态，在不同地理区域的人群中，以及这些多态可能对这些宿主感染EBOV的易感性产生的影响。这将有望识别一些人群可能固有的遗传特征，从而增加人畜共患病和任何随后的人类传播事件的风险。这将使人们认识到在大爆发期间可能更有可能受到感染的人群，或者经历疾病严重性增加的人群。因此，可以了解公共卫生政策，以便改进今后的暴发管理和应对措施。据推测，由于疫情传统上仅限于非洲，非洲体面人群可能表现出与其他人群不同频率的某些突变，这些突变可能具有更强的内在抵抗力，因此更容易受到感染。此外，还将努力尝试并确定影响EBOV跨其他宿主进入的NPC1多态，特别是灵长类和蝙蝠物种。这将有助于确定影响EBOV进入的物种决定因素，从而提供对野生溢出事件的更好理解，这些事件已被证明与过去的人类疫情直接相关。由于病毒的进化可以对疫情传播和疾病严重程度产生重大影响，除了环境和公共卫生等其他因素外，该项目的最终目标将是确定EBOV的长期进化对其传染性和趋向性的影响。这将通过对已合成的祖先节点序列进行表征，并将其传染性与现有序列进行比较，这些序列代表了自1976年以来在不同细胞系中发生的所有EBOV疫情，包括人类和蝙蝠。这将是在未完成广泛抽样的疫情中衡量EBOV进化速度的重要指标。它还将为未来疗法的发展提供信息，以确保它们对导致过去暴发的所有主要菌株变种有效，并提供更多证据表明果蝠是宿主物种。

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.