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Sequencing Study Reveals Relationships, Roots of Resistance for Russian Tuberculosis

NEW YORK (GenomeWeb News) – A new Nature Genetics study hints that a combination of ineffective control strategies and new adaptations by Mycobacterium tuberculosis populations have contributed to the scourge of multi-drug resistant tuberculosis cases in Russia.

An international team led by investigators in the UK did whole-genome sequencing on 1,000 of the isolates prospectively collected from TB patients in the Russian city of Samara during a two-year period. The sequence data made it possible to retrace relationships of isolates in that region with one another and with those in other parts of the world, while providing insights into the genetic roots of drug resistance in the region.

For instance, the researchers tracked down secondary mutations in some isolates that are suspected of mitigating the usual dip in fitness associated with the acquisition of mutations that boost drug resistance. That type of information is expected to help in designing future programs for treating drug-resistant TB and curbing its spread.

"The combination of drug resistance and compensatory mutations displayed by the major clades confers clinical resistance without compromising fitness and transmissibility, showing that, in addition to weaknesses in the TB control program, biological factors drive the persistence and spread of [multi-drug resistant] and [extensively drug-resistant] tuberculosis in Russia and beyond," senior author Francis Drobniewski, a public health and infectious disease researcher affiliated with the Queen Mary University of London and Imperial College London, and colleagues wrote.

On average, roughly one-fifth of individuals with recurrent TB are infected with M. tuberculosis strains that can withstand several first-line antibiotics. Those multi-drug resistant isolates are also turning up in a small but significant fraction of new TB cases, the researchers noted, and are especially common in central Asia and Eastern Europe.

Drug resistance doesn't stop there. At the moment, some 9 percent of TB cases involve M. tuberculosis isolates that are "extensively drug-resistant," meaning they can withstand not only first-line antibiotics, but also some second-line treatments.

For their new look at the genetics behind the development and spread of drug resistant M. tuberculosis, authors of the current study focused on an area in Russia with high rates of both multi-drug resistant and extensively drug-resistant TB.

The researchers did whole-genome sequencing on 1,000 of the 2,348 M. tuberculosis isolates that had been obtained from TB patients treated in Samara between 2008 and 2010. That set is believed to accurately reflect features of the TB bugs circulating in that area, they explained.

"[W]e used whole-genome sequencing to investigate the molecular mechanisms underlying resistance, fitness compensation, and positive epistasis that together determine the transmissibility and prevalence of drug-resistant strains," the study authors wrote.

Compared to the M. tuberculosis reference genome, the isolates contained nearly 32,500 SNPs. Those variants contributed to the team's subsequent phylogenetic analysis of the M. tuberculosis isolates appearing in that region and beyond, revealing four main M. tuberculosis lineages: a Beijing lineage, a Euro-American lineage, a Central Asian lineage, and a lineage linked to East Africa and India.

The majority of the Russian isolates — more than 64 percent — clustered within the lineage from Beijing. Most of the remaining isolates belonged to a Euro-American with relatively high genetic diversity, while a few isolates fell in the Central Asian or East African-Indian lineages.

When they compared the newly sequenced isolates to M. tuberculosis sequences generated for a past study of London TB patients carrying isolates from diverse origins, the researchers saw that many Russian bugs in the Beijing lineage grouped into what they dubbed the East European sub-lineage (itself made up of two main clades).

Across the entire set of Russian samples, the group saw signs of pronounced drug resistance across almost all of the M. tuberculosis clades considered and in almost half of the individual isolates.

Of those, 16 percent were classified as extensively drug resistant. Meanwhile, most of the multi-drug resistant isolates carried mutations affecting response to an antibiotic called kanamycin that are suspected of contributing to a boost in virulence.

While the advent of new mutations may make M. tuberculosis less prone to various drug treatments, such changes are not always a total boon for the bug, the team noted.

For instance, past research has shown that resistance-related mutations can compromise M. tuberculosis growth in ways that may or may not be overcome by subsequent, compensatory mutations, which can influence how resistant bugs move in host populations.

In this case, for instance, researchers found that rifampicin resistance arising from mutations to a gene called rpoB were often accompanied by alterations in rpoA and rpoC genes that are predicted to stymie some of the growth defects arising from that resistance mutation.

"As more resistance-conferring loci are identified and the phenotypic effects of multiple mutations and strain background are elucidated," they wrote, "the public health value of routine whole-genome sequencing for the diagnosis of drug resistance will increase, although it may vary depending on prevalence and likely exposure to resistant strains."

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