Shorten, R.J.; (2011) The molecular epidemiology of Mycobacterium tuberculosis in north London. Doctoral thesis , UCL (University College London).

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Abstract

It is estimated that one third of the world‘s population are infected with the bacterium M. tuberculosis and approximately 9.4 million new cases of tuberculosis were diagnosed globally in 2008. Molecular tools, developed over the previous two decades, have allowed further in-depth study of this historic disease. Genotyping M. tuberculosis allows the study of evolutionary relationships and well as the routes of transmission of the organism between hosts. The pairing of genotyping with demographic data allows the analysis of the current trends of disease within a given patient population. Two genotyping methodologies (IS6110 RFLP and Mycobacterial Interspersed Repetitive Units – Variable Number Tandem Repeats (MIRU-VNTR)), alongside patient demographic data have been utilised for the TB population at the Royal Free Hospital, London. The data shows a patient population that is largely concordant with that seen in London as a whole; with the majority of TB patients being born outside of the UK and drug resistance rates that are higher than the national average. The acquisition of drug resistance-conferring mutations by M. tuberculosis is often presumed to be associated with a fitness cost. Here we investigate the fitness of isolates from two outbreaks involving large numbers of drug resistant strains. The first group of strains was found to be part of the ongoing north London isoniazid resistant outbreak. The data suggests that this outbreak consists of successful, closely related, circulating strains with heterogeneous resistance profiles and mutations and little or no associated fitness cost. The relationship between the biology of the organisms isolated from a cohort of TB patients who underwent a novel diagnostic interferon gamma release assay was investigated. Genotyping, ESAT-6 gene sequencing and gene expression assays suggest that varying immune response between individuals is driven by host factors rather than a characteristic of the strain of M. tuberculosis. This study shows that this geographic location in London is home to a diverse population of M. tuberculosis with a low rate of transmission. The demographic characteristics of the TB patients are largely concordant with the UK as a whole. These findings show that M. tuberculosis genotyping is critically important in the identification of suspected outbreaks and contamination events as well as the investigation of successful related strains and characteristic disease phenotypes. Genotyping can augment classic epidemiology and clinical practice to provide a holistic approach in the investigation, treatment and control of the global health problem. Understanding the biology and genomics of M. tuberculosis is how the enormous disease burden will be tackled.

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