Understanding differences in host responses to African swine fever virus

猪肉是世界上消费量第二大的肉类，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。持续的ASF泛动物源性疾病已导致全球数百万头猪被扑杀，目前正在亚洲、非洲、欧洲和加勒比地区蔓延。2018年，致病性ASF病毒（ASFV）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，并导致至少260亿英镑的巨大经济损失。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。目前的非洲猪瘟控制方法包括严格的生物安全、运动控制和扑杀受感染或暴露的动物，但这些都不足以控制全球范围内的传播。目前还没有安全有效的ASF疫苗被许可在主要猪肉生产国使用;缺乏ASF病毒和疫苗免疫生物学研究阻碍了疫苗的开发。为了开发控制ASFV的强大策略，需要确定宿主免疫机制。现场存在多种ASFV菌株。毒性ASFV在动物中诱导严重疾病，导致在十天内死亡，而低毒性ASFV引起轻度疾病，并且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这些毒株感染的器官中不同免疫细胞群体之间的复杂相互作用，确定高毒力和低毒力ASFV毒株诱导的不同临床结果背后的机制。了解这些差异将使我能够识别对未来ASFV控制方法很重要的细胞群和基因。我将使用器官来源的培养物来研究ASFV感染所涉及的免疫过程，以减少研究中的动物使用，这可能是未来研究的模型。我将首先比较猪免疫细胞对低毒力和高毒力ASFV感染的初级免疫应答。这将确定对ASFV感染的恢复力发展重要的细胞群。接下来，我将研究由低毒力和高毒力ASFV毒株引起的细胞死亡的差异。强毒ASFV感染导致许多对长期免疫至关重要的免疫细胞群死亡。因此，鉴定死亡的细胞群，无论是由于直接感染还是作为附带损害，都将有助于确定在未来的疫苗开发和疾病恢复力的选择性育种研究中应该关注哪些细胞群。最后，我将通过使用基因表达谱分析方法对有助于ASFV免疫的重要免疫细胞亚群进行鉴定，从而确定参与ASFV恢复力和抗性的基因。鉴定有助于ASFV免疫力的基因将有助于开发一组基因，以便在未来通过遗传选择或基因编辑开发ASF弹性动物时加以考虑。我的研究将导致减少研究中使用的动物，因为更好的知情实验，并填补了建立更好的ASF控制方法（通过疫苗或选择性育种）所需的免疫生物学研究的空白。这将最终改善牲畜健康，并为生计和全球粮食安全提供稳定性。

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.