Abstract

BackgroundKazakhstan remains a high-burden TB prevalence country with a concomitent high-burden of multi-drug resistant tuberculosis. For this reason, we performed an in depth genetic diversity and population structure characterization of Mycobacterium tuberculosis complex (MTC) genetic diversity in Kazakhstan with both patient and community benefit.MethodsA convenience sample of 700 MTC DNA cultures extracts from 630 tuberculosis patients recruited from 12 out of 14 regions in Kazakhstan, between 2010 and 2015, was independently studied by high-throughput hybridization-based methods, TB-SPRINT (59-Plex, n = 700), TB-SNPID (50-Plex, n = 543). DNA from 391 clinical isolates was successfully typed by two methods. To resolve the population structure of drug-resistant clades in more detail two complementary assays were run on the L2 isolates: an IS6110-NTF insertion site typing assay and a SigE SNP polymorphism assay.ResultsStrains belonged to L2/Beijing and L4/Euro-American sublineages; L2/Beijing prevalence totaled almost 80%. 50% of all samples were resistant to RIF and to INH., Subtyping showed that: (1) all L2/Beijing were “modern” Beijing and (2) most of these belonged to the previously described 94–32 sublineage (Central Asian/Russian), (3) at least two populations of the Central Asian/Russian sublineages are circulating in Kazakhstan, with different evolutionary dynamics.ConclusionsFor the first time, the global genetic diversity and population structure of M. tuberculosis genotypes circulating in Kazakhstan was obtained and compared to previous local studies. Results suggest a region-specific spread of a very limited number of L2/Beijing clonal complexes in Kazakhstan many strongly associated with an MDR phenotype.

Highlights

  • Kazakhstan remains a high-burden TB prevalence country with a concomitent high-burden of multidrug resistant tuberculosis

  • Lineage and intra-lineage Mycobacterium tuberculosis complex (MTC) genomics characterization using TB-SPRINT and TB-SNPID TB-SPRINT and TB-SNPID were respectively performed in France and in the Netherlands; each location was blinded to the results generated in the other location

  • In this study, we first performed an in depth genomic characterization of MTC isolates circulating in Kazakhstan over an extended sampling time frame (5 years) using a combination of high-throughput Nucleic-Acid PCRbased Amplication Tests (NAAT), with the global aim of simultaneously improving multidrug-resistant tuberculosis (MDR-TB) surveillance as well as providing the possibility to more accurately personalize TB treatment; complementary genomic characterization using IS6110 copy number characterization in the NTF region demonstrates the exclusive presence of Modern L2/Beijing strains in Kazakhstan

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Summary

Introduction

Kazakhstan remains a high-burden TB prevalence country with a concomitent high-burden of multidrug resistant tuberculosis. Apart from resistance to Rifampin (RIF) and Isoniazid (INH) that defines MDR, resistance to streptomycin (SRM), fluoroquinolones (FLQ) and other second-line injectable drugs (SLID) is common in MTC isolates from Russia and in Former Soviet Union (FSU) republics [1, 2]. Such a phenomenon creates a threat to the effective global control of TB infection. Kazakhstan, (together with Myanmar and Viet Nam) reported treatment success of more than 75% In this context, high-throughput predictive genotyping of drug susceptibility testing could complement and be a faster alternative to phenotypic DST or LIPAs, with high reliability if done in a limited number of certified reference laboratories. As such it could help monitoring as well as targeted DST testing for the bacteriologically confirmed cases (9597 in 2014) [5]

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