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Mycobacterium tuberculosis strains in New Zealand: phylogeny and structural biology

Abstract
Mycobacterium tuberculosis is an obligate human pathogen and is the primary causative agent of tuberculosis. New Zealand has a relatively low incidence of tuberculosis disease, however, Māori (the indigenous people of New Zealand) and Pacific People are disproportionally affected. Molecular typing shows that approximately two-thirds of M. tuberculosis isolates from New Zealand-born patients can be assigned to clusters of related strains. The largest M. tuberculosis cluster in New Zealand is known as the ‘Rangipo’ cluster and is predominantly found in Māori. This strain has been the source of several tuberculosis outbreaks over the last 30 years and anecdotal evidence suggests it may be particularly virulent. Two other large clusters, known as the ‘Southern Cross’ and ‘Otara’ clusters, most commonly occur in Pacific People. Here, whole genome sequencing, phylogenetics and structural biology were used to investigate evolutionary origins and functional consequences of genomic diversity in New Zealand M. tuberculosis clusters, with a particular focus on the Rangipo strain. Analysis of Rangipo strain non-synonymous single nucleotide polymorphisms (nsSNPs) identified bacterial genetic factors that may contribute to the high transmissibility of this strain. The F420-dependent oxidoreductase Rv2893 harbours a Rangipo-specific G72S mutation encoded by a nsSNP. H37Rv and Rangipo Rv2893 structures were solved and show the effect of this G72S mutation. Binding of the F420 cofactor was confirmed and characterised. SNP analyses also guided the optimisation of a diagnostic assay for rapid Rangipo strain classification at low cost and with high discriminatory power. Phylogenetic analyses revealed the Rangipo and Otara clusters belong to a larger M.tuberculosis clade of French/European origin that is also prevalent in indigenous populations in Canada. Molecular dating indicates dispersal of this clade to the South Pacific was driven by expanding European trade networks in the early 19th century and identifies host factors that have contributed to the dispersal and expansion of the Rangipo and Otara strains. Overall, these results show that relatively recent changes in host ecology have likely played a crucial role in driving the success of the Rangipo strain in New Zealand and point to bacterial genetic factors that may influence its virulence and thereby also contribute to its prevalence.
Type
Thesis
Type of thesis
Series
Citation
Claire Vignette, M. (2019). Mycobacterium tuberculosis strains in New Zealand: phylogeny and structural biology (Thesis, Doctor of Philosophy (PhD)). The University of Waikato, Hamilton, New Zealand. Retrieved from https://hdl.handle.net/10289/12420
Date
2019
Publisher
The University of Waikato
Rights
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