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Characterization of the Prevalence, Drug Resistance, and Virulence Factors of Mycobacterium tuberculosis Lineages of Hawaii
|Title:||Characterization of the Prevalence, Drug Resistance, and Virulence Factors of Mycobacterium tuberculosis Lineages of Hawaii|
|Authors:||Koster, Kent Jordan|
|Contributors:||Douglas, James T. (advisor)|
Whole Genome Sequencing
|Publisher:||University of Hawai'i at Manoa|
|Abstract:||Tuberculosis (TB) rates in the United States continue to decline, yet TB rates in the State of Hawaii perennially remain among the highest in the United States, primarily due to Hawaii’s continuous influx of immigrants from the Pacific and Asian regions. Accordingly, TB cases in Hawaii present a unique distribution of genetic lineages relative to the continental United States or Europe, with the Beijing and Manila families of Mycobacterium tuberculosis (Mtb) comprising roughly 2/3rds of Hawaii’s TB cases. This study seeks to better characterize the local prevalence, unique drug-resistance marker distributions, and unique genetic virulence factor mutations of the Beijing and Manila Mtb families. Both families demonstrated differences in the prevalence of specific drug-resistance alleles in an internationally-derived isolate set, which can guide the selection of markers for genetic drug-resistance screening when the local prevalence of Mtb families is known. katG 315 must be supplemented with the inhA promotor when screening Manila family isolates for isoniazid resistance, and rrs must be supplemented with the eis promotor when screening Beijing family isolates for aminoglycoside resistance. We further utilized whole genome sequencing (WGS) to identify “lineage-specific” single nucleotide polymorphisms (SNPs) in virulence factor genes. The Beijing family’s family-specific mutations included SNPs in sigG, pks5, and pks7, while the Manila family notably demonstrated truncation of whiB5. Additionally, we identified that CDC-standard fingerprinting methods (spoligotyping plus 24-loci MIRU-VNTR) are inadequate for resolving putative transmission clusters composed of Beijing or Manila family isolates. We determined that these families’ significantly lower Shannon diversity and evenness indices of MIRU-VNTR alleles caused this inadequacy. We then demonstrated the use of WGS for putative cluster resolution in Hawaii. We further propose how the demographics demonstrated by Hawaii’s Mtb families can inform allocation of TB control resources. The Beijing family requires a balanced distribution, while the Manila family allows for targeting of resources towards middle-aged males, and those who have resided in the county longer. These data both provide clinicians in the Pacific with tools to better control TB in the region, and provide TB researchers with additional genetic targets for further research on the region’s two dominant Mtb families.|
|Description:||Ph.D. Thesis. Ph.D. Thesis. University of Hawaiʻi at Mānoa 2019|
|Rights:||All UHM dissertations and theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission from the copyright owner.|
|Appears in Collections:||
Ph.D. - Microbiology|
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