Do respiratory epithelial cells ‘remember’ early life microbial exposure through epigenetic changes?

Abstract

The adaptive immune system was considered to be the sole arm of immunity that can form a memory of past infections. In recent years this paradigm has been contested, following discoveries that many innate immune cells display lasting changes in their responses to challenges as a consequence of previous infections. It was determined that these long-term changes in immune responses were possible due to epigenetic or metabolomic imprinting. This phenomenon was also observed in plants and invertebrates and termed ‘trained immunity’. Several cohort studies have linked severe respiratory syncytial virus (RSV) bronchiolitis in infancy with a higher risk of developing recurrent wheeze or childhood asthma, yet the pathomechanism behind this phenomenon remains undetermined. Here I hypothesise that RSV infection can epigenetically imprint airway epithelial cells (AECs), thus changing how these cells respond to subsequent challenges, which in turn provides a potential link between RSV infection and asthma development.

First, I established in vitro and in vivo AEC experimental systems that would allow us to test the presented hypothesis. Using an assortment of pathogen-associated molecular patterns (PAMPs) as stimuli, I established that a monolayer-based cell line system might not be suitable; however, an airliquid interface (ALI) culture system utilising primary human bronchial epithelial cells proved to be a promising experimental system.

Next, I used an in vivo murine model to investigate whether an RSV infection results in long-lasting changes in the responses of AECs to subsequent microbial stimuli. Despite promising cytokine/chemokine gene expression results of isolated murine AECs, I was unable to definitely confirm RSV-induced changes in response to subsequent stimulation at the transcriptional or protein level.

ivNevertheless, using the murine model, I observed that RSV infection causes lasting changes in the levels of major histocompatibility complex class I (MHC-I) and II (MHC-II) on the surface of AECs. Furthermore, as seen through histone modifications, I confirmed that RSV infection causes lasting epigenetic changes in AECs, including in the promoters of genes related to MHC biology.

Our results lay the basis for future investigation of trained immunity in AECs both in vitro and in vivo. I identified the limitations and benefits of several experimental systems. Importantly, I observed that RSV infection leads to lasting epigenetic and transcriptional changes of AECs that result in a prolonged increase in the levels of both MHC-I and MHC-II.