Investigating Trained Immunity in the Context of Respiratory Syncytial Virus Infection

呼吸道合胞病毒(RSV)感染是全球一岁以下儿童死亡的第二大原因。在全球范围内，呼吸道合胞病毒每年导致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康复，但他们在以后的生活中患上慢性喘息和/或过敏性哮喘的风险增加。这表明免疫系统必须保留对早期接触RSV的记忆，但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决定性特征，但最近的研究挑战了这一教条，现在很明显，天然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；这一过程被称为训练免疫。人们认为先天记忆可能储存在表观基因组中。在这个项目中，我的目标是剖析先天免疫记忆应对RSV感染的细胞和分子基础。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在RSV感染期间和之后肺单核吞噬细胞(MNPs)及其相关生态位的动态和异质性。在确定了这些群体中的异质性后，我将绘制这些亚集的表观基因组图，以调查它们是否保留了对病毒感染的记忆。最后，在表观遗传学分析的指导下，我将进行功能研究，以深入了解晚年发生肺部后遗症风险增加的机制。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，我可以找到新的治疗靶点来减轻长期效果。

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.