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Title: Analysis of epigenetic changes arising during challenge with Streptococcus pneumoniae
Author: Cole, Joby
ISNI:       0000 0004 7428 2450
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2018
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Streptococcus pneumoniae is the leading cause of community acquired pneumonia. The pathogenesis of pneumococcal disease is not fully understood. Nasopharyngeal colonisation precedes pneumococcal disease and is influenced by the effectiveness of innate immune responses. As the macrophage is a key component in the innate immune response, the interaction between S. pneumoniae and the macrophage will be crucial in controlling susceptibility to pneumococcal disease. It is increasingly recognised that epigenetic mechanisms play key roles in the host pathogen interaction. Mass spectrometry has emerged as a powerful tool for the study of global changes in histone post-translational modifications (PTM) one of the key epigenetic mechanisms. I hypothesised that S. pneumoniae induces immediate changes in the host's epigenome by altering histone post-translational modifications, in turn regulating the innate immune responses by modulating gene expression and may explain some of the variation observed in the susceptibility to invasive pneumococcal disease. I established a proteomic approach to determine the extent and nature of PTMs in primary human macrophages following challenge with S. pneumoniae and the contribution of pneumolysin, a key virulence factor, to changes in histone PTMs following bacterial challenge of MDMs. This illustrated that the relative abundance of several histone PTMs is modified in response to challenge with S. pneumoniae. I demonstrated that the bacterial virulence factor pneumolysin causes significant changes in both gene expression (503 differentially expressed genes) and protein expression in primary MDMs. Finally, I used RNA-Seq and ChIP-Seq, to attempt to determine the relationship between gene expression levels and PTMs of the associated histones. These analyses demonstrated a number of innate immune response genes to be differentially enriched, demonstrating the role of epigenetic regulation of gene expression associated with the innate immune response upon challenge with S. pneumoniae.
Supervisor: Dockrell, David ; Dickman, Mark Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available