Mechanism and functional consequences of Streptococcus pneumoniae chromatin remodeling of epithelial tissue

ongoing

Streptococcus pneumoniae is a pathobiont that is a top 10 WHO priority pathogen. Whilst it is commonly carried in the nasal cavity of healthy populations, it also causes invasive disease in vulnerable populations causing pneumoniae, meningitis, and septicaemia. However, the host factors involved in maintaining colonisation or triggering an immune response are currently unknown, and my research project aims to address this knowledge gap. In line with the expertise of the Hamon lab, the project will focus on bacteria-induced histone modifications which corelate with altered host gene expression. Following on the discovery that a colonising and asymptomatic strain of S. pneumoniae activates the histone demethylase KDM6B for immune homeostasis, the project will characterise the KDM6B-mediated response at the molecular level in a physiological model of nasal epithelium. Specifically, the research objectives are to: 1) Identify KDM6B binding partners during S. pneumoniae challenge 2) Define the nasal tissue response to S. pneumoniae 3) Characterize the KDM6B-mediated nasal tissue response to the bacteria The host laboratory has a powerful model of reconstituted nasal epithelium model in which responses to a colonising or an invasive strain of S. pneumoniae can be evaluated. I will use and gain expertise in cutting edge techniques such as mass spectrometry to determine KDM6B binding partners and single-cell RNA sequencing along with spatial transcriptomic technology (MERFISH) to analyse host cell responses at the single cell level. The field of bacteria mediated histone modifications is in its infancy and offers a large margin of discovery. Altogether this project will advance our understanding of the signals and pathways that regulate the balance between homeostasis and infection and will identify and characterise original mechanisms of host chromatin-bacteria cross talk which could be targeted for therapeutic purposes.