AbstractStaphylococcus aureus is a highly adaptable organism, which has established itself as one the most important pathogens worldwide. It has co-evolved with humans adapting to life within the host as well as the interventions targeted to eradicate it. Despite its notoriety as a pathogen one of its natural habitats is as a commensal on the human skin. The overarching aim of this project was to understand the genetic basis of this organism’s adaptation in the face of human intervention and influencing its survival in the human host, specifically during colonisation of the skin.
From humankind’s perspective arguably this organism’s most significant adaptation is the development of drug resistance. Methicillin resistant Staphylococcus aureus (MRSA) was first observed in 1960, less than one year after the introduction of the drug into clinical practice. Previous epidemiological and genetic evidence has always suggested that MRSA arose around this period, when the mecA gene encoding methicillin resistance carried on a Staphylococcal cassette chromosome mec (SCCmec) element, was acquired by S. aureus. In this work whole genome sequencing of a collection of the very first ever identified MRSA isolates was used to reconstruct the evolutionary events leading to the emergence of the archetypal MRSA lineage. This analysis revealed that S. aureus acquired the type I SCCmec element almost fourteen years prior to the first clinical use of methicillin, as a single horizontal event, and with its subsequent propagation leading to the genesis of MRSA.
Staphylococcus aureus colonisation is a characteristic feature of the inflammatory skin disease atopic eczema (AE). In AE disease exacerbations are associated with an increased burden of this pathogen. Despite this the colonisation dynamics of S. aureus during disease flare eczema are poorly understood. Therefore the remainder of this body of work sought to genetically interrogate AE disease-associated S. aureus isolates to gain further understanding of how this organism contributes to the disease pathogenesis. Firstly by characterising genetic heterogeneity arising during colonisation in periods of disease flare in children with AE, in direct comparison to healthy children asymptomatically nasally colonised, looking for evidence of micro-evolutionary change suggestive of adaptation to the host. Secondly by comparing isolates from a cohort of AE cases to childhood nasal carriers to characterise the population structure and genetic content of AE disease vs. carriage isolates. These works demonstrated that colonisation in AE during disease flare is the result of a clonal expansion of a single strain type, mirroring the colonisation dynamics found in nasal carriers. In AE cases evidence of clinically relevant adaptive mutations were identified which were linked to prolonged periods of carriage, and included examples affecting global regulators of virulence and antimicrobial resistance. This analysis also revealed segregation in the genetic backgrounds of strains preferentially colonising AE skin in comparison to nasal epithelium, and evidence of the impact of prescribing practises between the disease populations.
|Date of Award||2016|
|Add any sponsors of the thesis research||Wellcome Trust|
|Supervisor||Charlotte Proby (Supervisor) & Matthew T. G. Holden (Supervisor)|
Genomic investigation into the evolution of <i>Staphylococcus aureus</i> and the micro-epidemiology of <i>Staphylococcus aureus </i>in atopic eczema
Harkins, C. P. (Author). 2016
Student thesis: Doctoral Thesis › Doctor of Philosophy