Genetic variations of <italic>Mycobacterium tuberculosis</italic> clinical isolates and their epidemiological and clinical relevance.
Kong, Ying
2006
Abstract
Tuberculosis (TB) is a longstanding public health problem, causing morbidity and mortality worldwide. Exploring the genetic variations among clinical isolates and analyzing their associations with epidemiological and clinical characteristics of patients may identify potential <italic>M. tuberculosis</italic> virulence factors, thereby to develop better diagnostic tools, therapeutics, and vaccines for TB control. We used a five-year population-based TB surveillance database and epidemiologically and clinically well-characterized isolate collection to investigate genetic variations of phospholipase C (PLC) encoding genes, the prevalence of three principal genetic groups based on the single nucleotide polymorphisms of <italic>katG</italic> codon 463 and <italic>gyrA</italic> codon 95, and the regions of difference (RDs), and to analyze their clinical and epidemiological relevance. The major findings from the four studies of this dissertation are the following: (1) insertion and deletion related-mutation of the <italic>plcD</italic> gene is associated with extrathoracic TB after adjusting for <italic>plcABC</italic> genotypes, HIV sero-status, race, and gender, suggesting that <italic>plcD</italic> gene may play a more important role in developing thoracic TB than it does in extrathoracic TB; (2) the infection of the principal group 1 isolates is associated with extrathoracic TB after adjusting for <italic>plcD</italic> genotypes, HIV sero-status, race, and gender, suggesting that the group isolates may have special bacterial features favoring extrathoracic TB development; (3) nearly half of the group 1 isolates were obtained from patients of Asian origin, and about 80% patients of Asian origin were infected with the group 1 isolates, indicating that geographic separation may result in a stable relationship between a distinct <italic> M. tuberculosis</italic> subpopulation and its host population; (4) a concurrent deletion of RD105, RD181, and RD142, and a concurrent deletion of RD105, RD181, and RD150 were associated with extrathoracic TB, respectively, after adjusting for <italic>plcD</italic> genotypes, HIV sero-status, race, and gender; these RD deletions have the potential for being used to predict the clinical presentation of <italic>M. tuberculosis</italic> infection in the human host; and (5) the RD105 deletion is associated with Beijing/W lineage strains, thus can be used as a marker of Beijing/W lineage strains. This dissertation demonstrates that the integration of molecular techniques with epidemiological methodology is a useful approach to understand the roles of bacterial genes in the pathogenesis of TB.Subjects
Clinical Epidemiological Genetic Isolates Large-sequence Polymorphism Mycobacterium Tuberculosis Phospholipase C Relevance Variations
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