Microbiology & Immunology - Theses
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ItemComparative genomics of the Mycobacterium ulcerans and Mycobacterium marinum complex( 2012)Buruli ulcer is a neglected tropical disease which is prevalent in Western Africa. Its etiological agent, Mycobacteria ulcerans occurs in a wide range of hosts and environments across the world. In contrast to its progenitor Mycobacteria marinum, the bacteria and related strains produce a toxin mycolactone, an immunosuppressive polyketide which gives rise to its pathogenicity. Bacterial pathogenesis has a number of hallmarks such as; an evolutionary bottleneck, insertion sequence (IS) expansion, pseudogene increase, genome reduction, horizontal gene transfers (HGT) and adaption to a new niche. M. ulcerans shows all of these characteristics and is a fine model for gaining a deeper understanding of the mechanics of bacterial pathogenesis in general and specifically for M. ulcerans and related strains. This research analyses the genomic makeup of 35 isolates that produce mycolactone and five M. marinum isolates. Such analysis have recently become possible through the rapid technological development of high throughput sequencing (HTS) allowing whole genome sequences of all isolates to be compared and contrasted. Nucleotide level comparisons of the isolates has enumerated a core set of SNPs and allowed a detailed phylogeny of the isolates to be revealed showing the clonal nature of the mycolactone producing isolates that have evolved from the marine dwelling M. marinum. Also highlighted were two distinct bottlenecks, both accompanied by IS expansion, genome reduction and HGT. The first bottleneck acquired the pMUM001 virulence plasmid that confers the ability to synthesis mycolactone. A second bottleneck resulted in the creation of the more pathogenic clonal groups of isolates present in Africa and Australia, which are responsible for the majority of global Buruli ulcer cases. Genome reduction has resulted in the loss of at least 185 genes with cell wall genes being overrepresented. The balance of the cell wall genes show further signs of adaptive selection suggesting remodelling of the cell wall in response to its new niche or environment. Locating the numerous ISs within the isolates indicated the virulence plasmid pMUM001 to be the likely source of the ISs, which in turn confers genome plasticity on the bacteria. A most recent common ancestor of M. marinum has given rise to M. ulcerans and all mycolactone-producing mycobacteria that are specialized variants and have evolved to live in niche environments. Analysis of the genes that have been lost, the genes retained, and the genes now under selective pressure suggest these environments might be dark, aerobic, and extracellular. The bacterial characteristics of M. ulcerans such as, slow growth, production of an immune suppressor, cell wall remodelling, loss or modification of cell wall antigens, and biofilm-forming ability all provide a survival advantage in these environments. This research provides a detailed investigation into the genetic makeup and biological impact of this group of Mycobacteria and will allow better understanding of the transmission of Buruli ulcer and their reservoirs.