Understanding differences in host responses to African swine fever virus

猪肉是世界上消费第二多的肉类，预计到2030年将占全球肉类市场的34%。然而，全球猪肉供应受到非洲猪瘟(ASF)的威胁。正在进行的ASF恐慌已导致全球数百万头猪被扑杀，目前正在亚洲、非洲、欧洲和加勒比海地区传播。2018年，致病性ASF病毒传播到中国(世界上最大的猪肉生产国)，导致全国至少一半的猪群损失。这破坏了全球猪肉市场的稳定，造成了至少260亿GB的巨大经济损失。ASFV感染猪和野猪，通常通过接触受感染的动物和受污染的表面传播。目前的ASF控制方法包括严格的生物安全、行动控制和对受感染或暴露的动物的扑杀，但这些方法不足以控制全球传播。目前还没有安全有效的ASF疫苗获准在主要猪肉生产国使用；ASF病毒和疫苗免疫生物学研究的缺乏阻碍了疫苗的开发。为了制定强有力的策略来控制ASFV，需要确定宿主免疫机制。田间存在多种ASFV毒株。强毒ASFV在动物身上引起严重疾病，导致10天内死亡，而低毒力ASFV会导致轻微疾病，动物通常在感染后恢复。对感染的免疫需要不同免疫细胞以复杂和动态的方式参与。我的主要目标是通过研究感染这些毒株的器官中不同免疫细胞群之间的复杂相互作用，确定高毒力和低毒力ASFV毒株导致不同临床结果的机制。了解这些差异将使我能够确定对未来ASFV控制方法重要的细胞群体和基因。我将使用器官来源的培养来研究ASFV感染所涉及的免疫过程，以减少研究中使用的动物，这可能是未来研究的一个模型。我将首先比较猪免疫细胞对低毒力和高毒力ASFV感染的初级免疫反应。这将确定对发展对ASFV感染的抵抗力很重要的细胞群体。接下来，我将研究低毒力和高毒力ASFV毒株引起的细胞死亡的差异。感染强毒ASFV会导致许多对长期免疫至关重要的免疫细胞群死亡。因此，识别死亡的细胞群体，无论是由于直接感染还是作为附带损害，将有助于确定哪些细胞群体应该在未来的疫苗开发和选择性育种研究中作为抗病能力的重点。最后，我将通过使用对ASFV免疫有贡献的重要免疫细胞亚群的基因表达谱方法来识别与ASFV的韧性和抗药性有关的基因。识别影响ASFV免疫的基因将有助于开发一组基因，通过基因选择或基因编辑，在未来ASF恢复力动物的发展中考虑这些基因。我的研究将减少研究中使用的动物，因为有了更好的知情实验，并填补了建立更好的ASF控制方法所需的免疫生物学研究的空白(通过疫苗或选择性育种)。这最终将改善牲畜健康，并为生计和全球粮食安全提供稳定。

Pork is the second most consumed meat in the world and is projected to account for 34% of the global meat market by 2030. However, the global supply of pork is threatened by African swine fever (ASF). The ongoing ASF panzootic has resulted in the culling of millions of pigs worldwide and is currently spreading in Asia, Africa, Europe, and the Caribbean. In 2018, the causative ASF virus (ASFV) spread into China (the world's largest pork producer) resulting in a loss of at least half of the nation's pig herd. This destabilised global pork markets and resulted in huge economic losses of at least £26 billion. ASFV infects pigs and wild boar and is typically transmitted through exposure to infected animals and contaminated surfaces. Current ASF control methods involve strict biosecurity, movement control and culling of infected or exposed animals, but these are insufficient to control the spread globally. There are no safe and effective vaccines for ASF that are licensed for use in major pork producing countries; the lack of ASF viral and vaccine immunobiology research has hampered vaccine development. To develop robust strategies to control ASFV, host immunity mechanisms need to be identified. Multiple strains of ASFV exist in the field. Virulent ASFV induces severe disease in animals that results in death within ten days, whilst low virulent ASFV causes mild disease and animals typically recover after infection. Immunity to infection requires the participation of different immune cells in a complex and dynamic manner. My key goal is to identify mechanisms behind the different clinical outcomes induced by ASFV strains of high and low virulence by investigating the complex interactions between diverse immune cell populations in organs infected by these strains. Understanding these differences will allow me to identify cell populations and genes that are important for future ASFV control approaches. I will use organ-derived cultures to study the immune processes involved in ASFV infection to reduce animal use in research, which could be a model for future research. I will first compare the primary immune responses of pig immune cells to low and high virulent ASFV infection. This will identify cell populations that are important for the development of resilience to ASFV infection. Next, I will investigate the differences in cell death caused by low and high virulent ASFV strains. Infection with virulent ASFV results in death of many immune cell populations essential for long-term immunity. Hence, the identification of cell populations dying, either due to direct infection or as collateral damage, will be useful to determine which cell populations should be focussed on in future vaccine development and selective breeding studies for disease resilience. Lastly, I will identify genes that are involved in resilience and resistance to ASFV by using gene expression profiling methods on important immune cell subsets that contribute to ASFV immunity. Identification of genes contributing to ASFV immunity will help to develop a panel of genes to be considered in future development of ASF resilient animals through genetic selection or gene editing. My research will lead to a reduction of animals used in research due to better informed experiments and fill the gaps in immunobiology research needed to establish better ASF control methods (through vaccines or selective breeding). This will ultimately improve livestock health and provide stability for livelihoods and global food security.