Investigating Trained Immunity in the Context of Respiratory Syncytial Virus Infection

呼吸道合胞病毒（RSV）感染是全世界1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造成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过来，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。尽管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，现在很清楚，先天免疫细胞可能“记住”某些炎症事件，这可能对它们的功能有长期影响；这个过程被称为训练免疫。据认为，先天记忆可能储存在“表观基因组”中。在这个项目中，我的目标是剖析应答RSV感染的先天免疫记忆的细胞和分子基础。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（MNPs）及其相关生态位的动力学和异质性。在确定了这些人群的异质性后，我将绘制这些亚群的表观基因组图，以研究它们是否保留了病毒感染的记忆。最后，在这种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病毒感染在这些细胞上的印记的长期变化，我可以找到新的治疗靶点来减轻长期影响。

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.