Investigating Trained Immunity in the Context of Respiratory Syncytial Virus Infection

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.