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

Background
Airway epithelial cells (EC) are the lung’s first line of defense against environmental stimuli and infectious agents, and are the source of a range of mediators which induce or suppress anti-viral responses and inflammation in respiratory viral infection and asthma. Early-life exposures are key to determining subsequent responses to environmental stimuli; e.g. exposure to a bacterial endotoxin-(LPS-)high farming environment results in upregulation of the EC-marker A20, which in turn reduces EC-responses to subsequent allergen exposure (Schuijs, 2015, Science), and reduced prevalence of asthma (Stein, 2016, NEJM). Conversely, early life severe respiratory syncytial virus infection gives a significantly increased risk of developing asthma, through mechanistic pathways that are insufficiently characterized.

We hypothesise that early-life stimuli (bacteria, viruses, allergens) cause epigenetic changes in EC, leading to increased or decreased inflammatory, anti-viral or pro-allergic responses after subsequent exposure. We aim to determine the nature of these changes, and how these could be modulated to prevent the development of recurrent viral wheeze and allergic asthma.

About the Project
This PhD project will use preclinical in vivo and human in vitro models, stimulating EC with viral and bacterial stimuli, then challenging these cells after prolonged intervals with secondary stimuli to see how primary stimuli change subsequent inflammatory and anti-viral EC-responses. Building on models of ‘EC- memory’ we have already developed and are currently characterizing, the project will test the hypothesis that ‘EC-memory’ is mediated by epigenetic modification of response genes, notably changes in DNA-methylation. Human and mouse EC from above experiments will be analysed for DNA-methylation by pyrosequencing of candidate gene promoters.

This project will provide excellent PhD-training opportunities through a range of different experimental approaches from murine in vivo work to human in vitro/ex vivo cell culture. Techniques involved will include animal handling, experimental procedures and dissection; virus culture (RSV-stock); complex cell culture; genetic and protein multiplex assays; bioinformatic analyses; and epigenetic studies.

This project aims to identify pathways by which EC become hyper- or hypo-sensitive to subsequent stimuli, contributing to the development of recurrent viral wheeze and asthma. It thus has the potential, based on the results, to enable us to design better agents/strategies to combat the development of these conditions, ultimately improving the lives of children and adults with recurrent viral lower respiratory tract infections and asthma.

About the Research Group
The research group is located in the University of Edinburgh / MRC Centre for Inflammation Research; a world-class research environment at the interface between biological and medical science, with multidisciplinary groupings focused on inflammation, infection, disease and repair. The Centre is based within the Edinburgh Medical School in the outstanding facilities of the Queen’s Medical Research Institute at the site of the Royal Infirmary of Edinburgh hospital, maximising future translational opportunities.