Abstract
Australia has a low tuberculosis incidence rate with most cases occurring among recent immigrants. Given suboptimal cluster resolution achieved with 24-locus mycobacterium interspersed repetitive unit (MIRU-24) genotyping, the added value of whole genome sequencing was explored. MIRU-24 profiles of all Mycobacterium tuberculosis culture-confirmed tuberculosis cases diagnosed between 2009 and 2013 in New South Wales (NSW), Australia, were examined and clusters identified. The relatedness of cases within the largest MIRU-24 clusters was assessed using whole genome sequencing and phylogenetic analyses. Of 1841 culture-confirmed TB cases, 91.9% (1692/1841) had complete demographic and genotyping data. East-African Indian (474; 28.0%) and Beijing (470; 27.8%) lineage strains predominated. The overall rate of MIRU-24 clustering was 20.1% (340/1692) and was highest among Beijing lineage strains (35.7%; 168/470). One Beijing and three East-African Indian (EAI) clonal complexes were responsible for the majority of observed clusters. Whole genome sequencing of the 4 largest clusters (30 isolates) demonstrated diverse single nucleotide polymorphisms (SNPs) within identified clusters. All sequenced EAI strains and 70% of Beijing lineage strains clustered by MIRU-24 typing demonstrated distinct SNP profiles. The superior resolution provided by whole genome sequencing demonstrated limited M. tuberculosis transmission within NSW, even within identified MIRU-24 clusters. Routine whole genome sequencing could provide valuable public health guidance in low burden settings.
Highlights
Mycobacterium tuberculosis is a highly successful human pathogen
The mean age of patients infected with Beijing and East-African Indian (EAI) lineage strains was similar (43 and 45 years respectively, p = 0.02), but Beijing strains caused disease with a bi-phasic age distribution being most common in young adults (15-29yrs) and in older people (>60yrs)
whole-genome sequencing (WGS) demonstrated that large M. tuberculosis genotype clusters identified with routine MIRU24 typing were not indicative of local transmission in this low TB incidence setting dominated by imported disease
Summary
Mycobacterium tuberculosis is a highly successful human pathogen. Estimates suggest that up to a third of global people are infected and that 9 million developed active disease in 2014 [1]. Seven M. tuberculosis strain lineages have been identified with distinct geographic distribution patterns, shaped by ancient human migration pathways [2,3]. More recent migration patterns and increased population mobility are reshaping these geographic distributions. Traditional genotyping methods such as mycobacterial interspersed repetitive unit (MIRU) analysis provided new insight into pathogen diversity and strain-specific transmission dynamics [4]. Different M. tuberculosis strain lineages have been associated with variable virulence, transmissibility, disease phenotypes and drug resistance profiles [5,6,7]. Molecular epidemiology studies confirmed the transmissibility of drug-resistant strains and highlighted the importance of re-infection in tuberculosis (TB) endemic settings with uncontrolled transmission [8,9]. More recently the availability of whole-genome sequencing (WGS) has provided unprecedented strain resolution to enhance our understanding of M. tuberculosis evolution and transmission [10,11]
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