Molecular Epidemiology and Genetic Diversity of Multidrug-Resistant Mycobacterium tuberculosis Isolates in Bangladesh

Abstract

Although the number of multidrug-resistant (MDR) tuberculosis (TB) cases is high overall, a major gap exists in our understanding of the molecular characteristics and transmission dynamics of the MDR Mycobacterium tuberculosis isolates circulating in Bangladesh. The present study aims to characterize the MDR-TB isolates of Bangladesh and to investigate the mode of transmission. A total of 544 MDR-TB isolates were obtained from a nationwide drug-resistant TB surveillance study conducted between October 2011 and March 2017 covering all geographic divisions of Bangladesh. The isolates were characterized using TbD1 deletion analysis, spoligotyping, and mycobacterial interspersed repetitive-unit-variable-number tandem-repeat (MIRU-VNTR) typing. Deletion analysis showed that 440 (80.9%) isolates were the modern type, while the remainder were the ancestral type. The largest circulating lineage was the Beijing type, comprising 208 isolates (38.2%), followed by T, EAI, and LAM with 93 (17.1%), 58 (10.7%), and 52 (9.5%) isolates, respectively. Combined MIRU-VNTR and spoligotyping analysis demonstrated that the majority of the clustered isolates were of the Beijing and T1 lineages. The overall rate of recent transmission was estimated at 33.8%. In conclusion, the MDR M. tuberculosis isolates circulating in Bangladesh are mostly of the modern virulent type. The Beijing and T lineages are the predominant types and most of the transmission of MDR-TB can be attributed to them. The findings also suggest that, along with the remarkable transmission, the emergence of MDR-TB in Bangladesh is largely due to acquired resistance. Rapid and accurate diagnosis and successful treatment will be crucial for controlling MDR-TB in Bangladesh. IMPORTANCE Multidrug-resistant TB is considered to be the major threat to tuberculosis control activities worldwide, including in Bangladesh. Despite the fact that the number of MDR-TB cases is high, a major gap exists in our understanding of the molecular epidemiology of the MDR-TB isolates in Bangladesh. In our study, we characterized and classified the MDR-TB isolates circulating in Bangladesh and investigated their mode of transmission. Our results demonstrated that the MDR M. tuberculosis isolates circulating in Bangladesh are mostly of the modern virulent type. The Beijing and T lineages are the predominant types and are implicated in the majority of MDR-TB transmission. Our findings reveal that, along with the remarkable transmission, the emergence of MDR-TB in Bangladesh is largely due to acquired resistance, which may be due to nonadherence to treatment or inadequate treatment of TB patients. Rapid diagnosis and adherence to an appropriate treatment regimen are therefore crucial to controlling MDR-TB in Bangladesh.

Keywords: Bangladesh; MDR-TB; MIRU-VNTR; Mycobacterium tuberculosis; molecular epidemiology; spoligotyping.

FIG 1

Minimum spanning tree (MST) illustrating the evolutionary relationships between 33 clusters of MDR M. tuberculosis spoligotype lineages. The circles represent clusters of M. tuberculosis isolates and are labeled with their specific spoligotype international type (SIT) numbers. The sizes of the circles are proportionate to the numbers of isolates in each cluster. The color code indicates the major lineages.

FIG 2

Cladogram showing the phylogenetic relationships among 544 MDR M. tuberculosis isolates as demonstrated by MIRU-VNTR and spoligotyping. The MIRU-VNTR plus web application was used to analyze the data, and FigTree software (http://tree.bio.ed.ac.uk/software/) was applied to construct the cladogram. The outer circular line with different colors denotes different spoligotype lineages, and the inner red bars indicate the clusters as determined by MIRU-VNTR and spoligotyping.

FIG 3

Distribution of different spoligotype lineages of 544 MDR M. tuberculosis isolates in different geographical region of Bangladesh. The distribution of lineages in each geographical region is shown in the map, as well as in the corresponding pie-chart. The map was generated using the software ‘QGIS2.10.1-Pisa’.

FIG 4

Distributions of MDR-TB spoligotype lineages in different time frames throughout the study period. Compared to other lineages, Beijing was the most prevalent throughout the study period and demonstrated a rising trend from around 30% in 2011 to 2013 to nearly 50% in 2015 to 2017.

FIG 5

Map of Bangladesh showing the distribution of clustered MDR M. tuberculosis isolates as determined by the MIRU-VNTR typing method. Each color and shape denotes a different cluster. The map was generated using the software ‘QGIS2.10.1-Pisa’.