Evolution and emergence of multidrug-resistant Mycobacterium tuberculosis in Chisinau, Moldova

Brown, Tyler S.; Eldholm, Vegard; Brynildsrud, Ola Brønstad; Osnes, Magnus N; Levy, Natalie S.; Stimson, James A.; Colijn, Caroline; Alexandru, Sofia; Noroc, Ecaterina; Ciobanu, Nelly; Crudu, Valeriu; Cohen, Ted; Mathema, Barun

doi:10.1099/mgen.0.000620

Cited by 9 publications

(7 citation statements)

References 25 publications

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“…Our findings are consistent with our earlier work in the Republic of Moldova, which highlighted the presence of highly drug resistant Ural lineage 4.2 strains that appeared to be readily transmitting within the population 13,36–38 . However, the R e estimates for Ural 4.2 strains reported here contrast with a recently published study that found that there was a reduced transmission fitness associated with multi-drug resistance in L4 strains in another former Soviet Union country 10 .…”

Section: Discussionsupporting

confidence: 93%

The recent rapid expansion of multidrug resistant strains ofMycobacterium tuberculosisUral lineage 4.2 in the Republic of Moldova

Chitwood,

Colijn,

Yang

et al. 2023

Preprint

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The projected trajectory of multidrug resistant tuberculosis (MDR-TB) epidemics depends on the reproductive fitness of circulating strains of MDRM. tuberculosis (Mtb). Previous efforts to characterize the fitness of MDRMtbhave found thatMtbstrains of the Beijing sublineage (Lineage 2.2.1) may be more prone to develop resistance and retain fitness in the presence of resistance-conferring mutations than other lineages. UsingMtbgenome sequences from all culture-positive cases collected over two years in Moldova, we estimate the fitness of Ural (Lineage 4.2) and Beijing strains, the two lineages in which MDR is concentrated in the country. We estimate that the fitness of MDR Ural strains substantially exceeds that of other susceptible and MDR strains, and we identify several mutations specific to these MDR Ural strains. Our findings suggest that MDR UralMtbhas been transmitting efficiently in Moldova and poses a substantial risk of spreading further in the region.

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Section: Discussionsupporting

confidence: 93%

The recent rapid expansion of multidrug resistant strains ofMycobacterium tuberculosisUral lineage 4.2 in the Republic of Moldova

Chitwood,

Colijn,

Yang

et al. 2023

Preprint

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“…Molecular epidemiological studies have shown that TB caused by the spread of TB strains may account for 35 to 40% (even as high as 70%) of TB cases ( 10 ). Increasing evidence shows that the spread of drug-resistant TB strains is an important driving factor for the epidemic of TB ( 11 , 12 ). In view of the transmission of MTB, previous studies have mostly focused on economically developed areas such as Shanghai and Shenzhen, where 73 and 25.2% of MDR patients were likely to be transmitted, respectively ( 13 , 14 ).…”

Section: Introductionmentioning

confidence: 99%

Whole-genome sequencing to characterize the genetic structure and transmission risk of Mycobacterium tuberculosis in Yichang city of China

Tao²,

Yu³

et al. 2023

Front. Public Health

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ObjectiveThe burden of both general and drug-resistant tuberculosis in rural areas is higher than that in urban areas in China. To characterize the genetic structure and transmission risk of Mycobacterium tuberculosis in rural China, we used whole genome sequencing to analyze clinical strains collected from patients in two counties of Yichang for three consecutive years.MethodsFrom 2018 to 2020, sputum samples were collected for cultures from patients with suspected tuberculosis in Yidu and Zigui county, and DNA was extracted from the positive strains for genome sequencing. The online SAM-TB platform was used to identify the genotypes and drug resistance-related mutations of each strain, establish a phylogenetic tree, and calculated the genetic distances between pairwise strains. Twelve single nucleotide polymorphisms (SNPs) were used as thresholds to identify transmission clusters. The risk of related factors was estimated by univariable and multivariable logistic regression.ResultsA total of 161 out of the collected 231 positive strains were enrolled for analysis, excluding non-tuberculous mycobacterium and duplicate strains from the same patient. These strains belonged to Lineage 2 (92, 57.1%) and Lineage 4 (69, 42.9%), respectively. A total of 49 (30.4%) strains were detected with known drug resistance-related mutations, including 6 (3.7%) multidrug-resistant-TB (MDR-TB) strains and 11 (6.8%) RIF-resistant INH-susceptible TB (Rr-TB) strains. Six of the MDR/Rr-TB (35.3%) were also resistant to fluoroquinolones, which made them pre-extensively drug-resistant TB (pre-XDR-TB). There were another seven strains with mono-resistance to fluoroquinolones and one strain with resistance to both INH and fluoroquinolones, making the overall rate of fluoroquinolones resistance 8.7% (14/161). A total of 50 strains (31.1%) were identified as transmission clusters. Patients under 45 years old (adjusted odds ratio 3.46 [95% confidential intervals 1.28–9.35]), treatment-naive patients (6.14 [1.39–27.07]) and patients infected by lineage 4 strains (2.22 [1.00–4.91]) had a higher risk of transmission.ConclusionThe drug resistance of tuberculosis in rural China, especially to the second-line drug fluoroquinolones, is relatively serious. The standardized treatment for patients and the clinical use of fluoroquinolones warrant attention. At the same time, the recent transmission risk of tuberculosis is high, and rapid diagnosis and treatment management at the primary care needs to be strengthened.

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“…Although the human T-cell epitopes in Mtb demonstrated conservative roles, there were two codons with three mutations (Ser315Arg and Ser315Thr of katG , and Thr2Ala of esxW ) in the T-cell epitopes under positive selection, exhibiting higher genetic diversity in specific T-cell epitopes. It was reported that esxW Thr2Ala is associated with increased transmissibility in Lineage 2 (2.2.1) Mtb strains ( Holt et al, 2018 ; Brown et al, 2021 ), and katG _S315R and katG _S315T are both highly reliable markers for isoniazid resistance ( World Health Organization, 2021 ). We speculate that Mtb strains bearing katG 315 mutations are beneficial for the pathogen escaping from isoniazid pressure and human T-cell recognition ( Coscolla et al, 2015 ), and the addition of esxW Thr2Ala increases the speed of the spread of isoniazid-resistant Mtb .…”

Section: Discussionmentioning

confidence: 99%

Identification of positively selected genes in Mycobacterium tuberculosis from southern Xinjiang Uygur autonomous region of China

Deng,

Wang,

Liu

et al. 2024

Front. Microbiol.

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BackgroundTuberculosis (TB), mainly caused by Mycobacterium tuberculosis (Mtb), remains a serious public health problem. Increasing evidence supports that selective evolution is an important force affecting genomic determinants of Mtb phenotypes. It is necessary to further understand the Mtb selective evolution and identify the positively selected genes that probably drive the phenotype of Mtb.MethodsThis study mainly focused on the positive selection of 807 Mtb strains from Southern Xinjiang of China using whole genome sequencing (WGS). PAML software was used for identifying the genes and sites under positive selection in 807 Mtb strains.ResultsLineage 2 (62.70%) strains were the dominant strains in this area, followed by lineage 3 (19.45%) and lineage 4 (17.84%) strains. There were 239 codons in 47 genes under positive selection, and the genes were majorly associated with the functions of transcription, defense mechanisms, and cell wall/membrane/envelope biogenesis. There were 28 codons (43 mutations) in eight genes (gyrA, rpoB, rpoC, katG, pncA, embB, gid, and cut1) under positive selection in multi-drug resistance (MDR) strains but not in drug-susceptible (DS) strains, in which 27 mutations were drug-resistant loci, 9 mutations were non-drug-resistant loci but were in drug-resistant genes, 2 mutations were compensatory mutations, and 5 mutations were in unknown drug-resistant gene of cut1. There was a codon in Rv0336 under positive selection in L3 strains but not in L2 and L4 strains. The epitopes of T and B cells were both hyper-conserved, particularly in the T-cell epitopes.ConclusionThis study revealed the ongoing selective evolution of Mtb. We found some special genes and sites under positive selection which may contribute to the advantage of MDR and L3 strains. It is necessary to further study these mutations to understand their impact on phenotypes for providing more useful information to develop new TB interventions.

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Evolution and emergence of multidrug-resistant Mycobacterium tuberculosis in Chisinau, Moldova

Cited by 9 publications

References 25 publications

The recent rapid expansion of multidrug resistant strains ofMycobacterium tuberculosisUral lineage 4.2 in the Republic of Moldova

The recent rapid expansion of multidrug resistant strains ofMycobacterium tuberculosisUral lineage 4.2 in the Republic of Moldova

Whole-genome sequencing to characterize the genetic structure and transmission risk of Mycobacterium tuberculosis in Yichang city of China

Identification of positively selected genes in Mycobacterium tuberculosis from southern Xinjiang Uygur autonomous region of China

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