Investigating Trained Immunity in the Context of Respiratory Syncytial Virus Infection

研究呼吸道合胞病毒感染背景下的训练免疫力

• 批准号: EP/X025071/1
• 负责人: Wouter T'Jonck
• 金额: $ 26万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FX025071%2F1
• 关键词: Investigating; Trained; Immunity; Context; Respiratory

Respiratory Syncytial virus (RSV) infection is the second largest cause of death in children under one year of age worldwide. Globally, RSV is responsible for 33 million episodes of acute lower respiratory infections in children each year. Although most children recover from this infection, they have an increased risk of developing chronic wheezing and/or allergic asthma later in life. This suggests that the immune system must retain a memory of this early exposure to RSV, however the cellular and molecular pathways underlying this memory remain poorly understood. Although immune memory is considered a defining feature of the adaptive immune system, recent work has challenged this dogma and it is now clear that innate immune cells may 'remember' certain inflammatory events and that this may have long-term effects on their function; a process termed trained immunity. It is thought that innate memory may be stored in the 'epigenome'.In this project, I aim to dissect the cellular and molecular basis of innate immune memory in response to RSV infection. To this end, I will first use state-of-the-art transcriptomics and proteomics techniques to track the dynamics and heterogeneity of lung mononuclear phagocytes (MNPs) and their associated niche during and after RSV infection. Having identified the heterogeneity within these populations, I will map the epigenome of these subsets to investigate whether they retain a memory of the viral infection. Finally, guided by this epigenetic analysis I will perform functional studies to gain insight into the mechanism behind the increased risk of developing pulmonary sequelae in later life. By elucidating the response of lung macrophages and their niche together with the long-term changes viral infection imprints on these cells, I could identify novel therapeutic targets to attenuate long-term effects.

呼吸道合胞病毒（RSV）感染是全世界一岁以下儿童死亡的第二大原因。在全球范围内，RSV每年导致3300万例儿童急性下呼吸道感染。虽然大多数儿童从这种感染中恢复，但他们在以后的生活中患慢性喘息和/或过敏性哮喘的风险增加。这表明免疫系统必须保留这种早期暴露于RSV的记忆，然而，这种记忆背后的细胞和分子途径仍然知之甚少。虽然免疫记忆被认为是适应性免疫系统的一个定义性特征，但最近的工作挑战了这一教条，现在很清楚先天免疫细胞可能会“记住”某些炎症事件，这可能会对它们的功能产生长期影响;这一过程称为训练免疫。先天性记忆被认为储存在表观基因组中，在这个项目中，我的目标是剖析先天性免疫记忆在RSV感染后的细胞和分子基础。为此，我将首先使用最先进的转录组学和蛋白质组学技术来跟踪RSV感染期间和之后肺单核吞噬细胞（MNP）及其相关生态位的动态和异质性。在确定了这些人群的异质性之后，我将绘制这些亚群的表观基因组，以研究它们是否保留了病毒感染的记忆。最后，在表观遗传学分析的指导下，我将进行功能研究，以深入了解晚年肺部后遗症风险增加背后的机制。通过阐明肺巨噬细胞及其生态位的反应以及这些细胞上病毒感染印记的长期变化，我可以确定新的治疗靶点以减轻长期影响。

项目成果

CSF1R-dependent macrophages in the salivary gland are essential for epithelial regeneration after radiation-induced injury

• DOI: 10.1126/sciimmunol.add4374
• 发表时间: 2023-11
• 期刊: Science Immunology
• 影响因子: 24.8
• 作者: John G. McKendrick;Gareth-Rhys Jones;Sonia S. Elder;Erin Watson;W. T’Jonck;Ella Mercer;Marlene S. Maga

CSF1R-dependent macrophages in the salivary gland are essential for epithelial regeneration following radiation-induced injury

• DOI: 10.1101/2022.06.12.495803
• 发表时间: 2022-06
• 期刊: bioRxiv
• 作者: J. McKENDRICK;G. Jones;Sonia S. Elder;Ella Mercer;M. Magalhaes;C. Rocchi;L. Hegarty;A. L. Johnson-A