Abstract
The transmission and persistence of Mycobacterium tuberculosis within high risk populations is a threat to tuberculosis (TB) control. In the current study, we used whole genome sequencing (WGS) to decipher the transmission dynamics and microevolution of M. tuberculosis ON-A, an endemic strain responsible for an ongoing outbreak of TB in an urban homeless/under-housed population. Sixty-one M. tuberculosis isolates representing 57 TB cases from 1997 to 2013 were subjected to WGS. Sequencing data was integrated with available epidemiological information and analyzed to determine how the M. tuberculosis ON-A strain has evolved during almost two decades of active transmission. WGS offers higher discriminatory power than traditional genotyping techniques, dividing the M. tuberculosis ON-A strain into 6 sub-clusters, each defined by unique single nucleotide polymorphism profiles. One sub-cluster, designated ON-ANM (Natural Mutant; 26 isolates from 24 cases) was also defined by a large, 15 kb genomic deletion. WGS analysis reveals the existence of multiple transmission chains within the same population/setting. Our results help validate the utility of WGS as a powerful tool for identifying genomic changes and adaptation of M. tuberculosis.
Highlights
Tuberculosis (TB) is an important cause of morbidity and mortality
Our analysis revealed the presence of six independent transmission chains and the presence of an Ontario A (ON-A) natural mutant, defined by a large genomic deletion that most likely emerged during the first ON-A TB outbreak in 2001
Other regulatory genes identified in the 15 kb deletion are the LuxR family regulator (Rv1358) which is regulated by Sigma-factor F (SigF) [33], a signal transduction regulatory gene (Rv1359) and a conserved gene (Rv1366) in which we identified a domain representative of RelA-SpoT superfamily, responsible for the regulation of ppGpp concentration. ppGpp is a modified nucleotide used by bacteria as intracellular messengers that respond to different environmental stresses [34,35]
Summary
Tuberculosis (TB) is an important cause of morbidity and mortality. World-wide, M. tuberculosis is responsible for more than 1 million deaths per year. TB outbreaks within homeless settings have been documented throughout North America [6,7,8,9]. One endemic strain, designated Ontario A (ON-A), has been circulating since at least 1997 in the urban homeless/underhoused population of Toronto, Canada and has been responsible for TB outbreaks in 2001 and 2004 with new cases identified every year [5,10]. The M. tuberculosis ON-A isolates are defined by a unique combined spoligotype and 24-locus MIRU-VNTR (24-MIRU) profile, while IS6110 RFLP generates pseudo-clusters among these strains [10]
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