Abstract
BackgroundIndia has the highest estimated burden of tuberculosis in the world, accounting for 21% of all tuberculosis cases world-wide. However, due to lack of systematic analysis using multiple markers the available information on the genomic diversity of Mycobacterium tuberculosis in India is limited.Methodology/Principal FindingsThus, 65 M. tuberculosis isolates from New Delhi, India were analyzed by spoligotyping, MIRU-VNTR, large deletion PCR typing and single nucleotide polymorphism analysis (SNP). The Central Asian (CAS) 1 _DELHI sub-lineage was the most prevalent sub-lineage comprising 46.2% (n = 30) of all isolates, with shared-type (ST) 26 being the most dominant genotype comprising 24.6% (n = 16) of all isolates. Other sub-lineages observed were: East-African Indian (EAI)-5 (9.2%, n = 6), EAI6_BGD1 (6.2%, n = 4), EAI3_IND, CAS and T1 with 6.2% each (n = 4 each), Beijing (4.6%, n = 3), CAS2 (3.1%, n = 2), and X1 and X2 with 1 isolate each. Genotyping results from five isolates (7.7%) did not match any existing spoligopatterns, and one isolate, ST124, belonged to an undefined lineage. Twenty-six percent of the isolates belonged to the TbD1+ PGG1 genogroup. SNP analysis of the pncA gene revealed a CAS-lineage specific silent mutation, S65S, which was observed for all CAS-lineage isolates (except two ST26 isolates) and in 1 orphan. Mutations in the pncA gene, conferring resistance to pyrazinamide, were observed in 15.4% of all isolates. Collectively, mutations in the rpoB gene, the katG gene and in both rpoB and katG genes, conferring resistance to rifampicin and isoniazid, respectively, were more frequent in CAS1_DELHI isolates compared to non-CAS_DELHI isolates (OR: 3.1, CI95% [1.11, 8.70], P = 0.045). The increased frequency of drug-resistance could not be linked to the patients' history of previous anti-tuberculosis treatment (OR: 1.156, CI95% [0.40, 3.36], P = 0.79). Fifty-six percent of all new tuberculosis patients had mutations in either the katG gene or the rpoB gene, or in both katG and rpoB genes.ConclusionCAS1_DELHI isolates circulating in New Delhi, India have a high frequency of mutations in the rpoB and katG genes. A silent mutation (S65S) in the pncA gene can be used as a putative genetic marker for CAS-lineage isolates.
Highlights
The Indian subcontinent has been a global hotspot for the growth and spread of the TB epidemic in recent times [1] and has served as the corridor of early world-wide dissemination of M. tuberculosis during the ancient era [2]
CAS1_DELHI isolates circulating in New Delhi, India have a high frequency of mutations in the rpoB and katG genes
A silent mutation (S65S) in the pncA gene can be used as a putative genetic marker for Central Asian (CAS)-lineage isolates
Summary
The Indian subcontinent has been a global hotspot for the growth and spread of the TB epidemic in recent times [1] and has served as the corridor of early world-wide dissemination of M. tuberculosis during the ancient era [2]. Mycobacterium tuberculosis genotypes from the Indian subcontinent have largely been described using, in most cases, single techniques to define bacterial diversity [3,4,5,6,7]. Such studies, important, underestimate the clonal diversity of M. tuberculosis. A study by Hanekom et al [13] suggests that there are discriminatory limitations to the available genotyping methods in high TBincidence areas and that the choice of appropriate MIRU-VNTR loci require further investigation in diverse M. tuberculosis lineages in low- and high TB-endemic countries. Due to lack of systematic analysis using multiple markers the available information on the genomic diversity of Mycobacterium tuberculosis in India is limited
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