Iron-related gene mutations driving global Mycobacterium tuberculosis transmission revealed by whole-genome sequencing
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SUBMITTER: Li Y
PROVIDER: S-EPMC10916221 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Project description:BackgroundThe toxin-antitoxin (TA) system plays a vital role in the virulence and pathogenicity of Mycobacterium tuberculosis (M. tuberculosis). However, the regulatory mechanisms and the impact of gene mutations on M. tuberculosis transmission remain poorly understood.ObjectiveTo investigate the influence of gene mutations in the toxin-antitoxin system on M. tuberculosis transmission dynamics.MethodWe performed whole-genome sequencing on the analyzed strains of M. tuberculosis. The genes associated with the toxin-antitoxin system were obtained from the National Center for Biotechnology Information (NCBI) Gene database. Mutations correlating with enhanced transmission within the genes were identified by using random forest, gradient boosting decision tree, and generalized linear mixed models.ResultsA total of 13,518 M. tuberculosis isolates were analyzed, with 42.29% (n = 5,717) found to be part of genomic clusters. Lineage 4 accounted for the majority of isolates (n = 6488, 48%), followed by lineage 2 (n = 5133, 37.97%). 23 single nucleotide polymorphisms (SNPs) showed a positive correlation with clustering, including vapB1 G34A, vapB24 A76C, vapB2 T171C, mazF2 C85T, mazE2 G104A, vapB31 T112C, relB T226A, vapB11 C54T, mazE5 T344C, vapB14 A29G, parE1 (C103T, C88T), and parD1 C134T. Six SNPs, including vapB6 A29C, vapB31 T112C, parD1 C134T, vapB37 G205C, Rv2653c A80C, and vapB22 C167T, were associated with transmission clades across different countries. Notably, our findings highlighted the positive association of vapB6 A29C, vapB31 T112C, parD1 C134T, vapB37 G205C, vapB19 C188T, and Rv2653c A80C with transmission clades across diverse regions. Furthermore, our analysis identified 32 SNPs that exhibited significant associations with clade size.ConclusionOur study presents potential associations between mutations in genes related to the toxin-antitoxin system and the transmission dynamics of M. tuberculosis. However, it is important to acknowledge the presence of confounding factors and limitations in our study. Further research is required to establish causation and assess the functional significance of these mutations. These findings provide a foundation for future investigations and the formulation of strategies aimed at controlling TB transmission.
| S-EPMC11322068 | biostudies-literature
Project description:BackgroundFatty acid metabolism greatly promotes the virulence and pathogenicity of Mycobacterium tuberculosis (M.tb). However, the regulatory mechanism of fatty acid metabolism in M.tb remains to be elucidated, and limited evidence about the effects of gene mutations in fatty acid metabolism on the transmission of M.tb was reported.ResultsOverall, a total of 3193 M.tb isolates were included in the study, of which 1596 (50%) were genomic clustered isolates. Most of the tuberculosis isolates belonged to lineage2(n = 2744,85.93%), followed by lineage4(n = 439,13.75%) and lineage3(n = 10,0.31%).Regression results showed that the mutations of gca (136,605, 317G > C, Arg106Pro; OR, 22.144; 95% CI, 2.591-189.272), ogt(1,477,346, 286G > C ,Gly96Arg; OR, 3.893; 95%CI, 1.432-10.583), and rpsA (1,834,776, 1235 C > T, Ala412Val; OR, 3.674; 95% CI, 1.217-11.091) were significantly associated with clustering; mutations in gca and rpsA were also significantly associated with clustering of lineage2. Mutation in arsA(3,001,498, 885 C > G, Thr295Thr; OR, 6.278; 95% CI, 2.508-15.711) was significantly associated with cross-regional clusters. We also found that 20 mutation sites were positively correlated with cluster size, while 11 fatty acid mutation sites were negatively correlated with cluster size.ConclusionOur research results suggested that mutations in genes related to fatty acid metabolism were related to the transmission of M.tb. This research could help in the future control of the transmission of M.tb.
| S-EPMC10691062 | biostudies-literature
Project description:BackgroundTwo-component systems (TCSs) assume a pivotal function in Mycobacterium tuberculosis (M.tuberculosis) growth. However, the exact regulatory mechanism of this system needs to be elucidated, and only a few studies have investigated the effect of gene mutations within TCSs on M.tuberculosis transmission. This research explored the relationship between TCSs gene mutation and the global transmission of (M.tuberculosis).ResultsA total of 13531 M.tuberculosis strains were enrolled in the study. Most of the M.tuberculosis strains belonged to lineage4 (n=6497,48.0%), followed by lineage2 (n=5136,38.0%). Our results showed that a total of 36 single nucleotide polymorphisms (SNPs) were positively correlated with clustering of lineage2, such as Rv0758 (phoR, C820G), Rv1747(T1102C), and Rv1057(C1168T). A total of 30 SNPs showed positive correlation with clustering of lineage4, such as phoR(C182A, C1184G, C662T, T758G), Rv3764c (tcrY, G1151T), and Rv1747 C20T. A total of 19 SNPs were positively correlated with cross-country transmission of lineage2, such as phoR A575C, Rv1028c (kdpD, G383T, G1246C), and Rv1057 G817T. A total of 41 SNPs were positively correlated with cross-country transmission of lineage4, such as phoR(T758G, T327G, C284G), kdpD(G1755A, G625C), Rv1057 C980T, and Rv1747 T373G.ConclusionsOur study identified that SNPs in genes of two-component systems were related to the transmission of M. tuberculosis. This finding adds another layer of complexity to M. tuberculosis virulence and provides insight into future research that will help to elucidate a novel mechanism of M. tuberculosis pathogenicity.
| S-EPMC10683263 | biostudies-literature
Project description:Mycobacterium tuberculosis is characterised by limited genomic diversity, which makes the application of whole genome sequencing particularly attractive for clinical and epidemiological investigation. However, in order to confidently infer transmission events, an accurate knowledge of the rate of change in the genome over relevant timescales is required.We attempted to estimate a molecular clock by sequencing 199 isolates from epidemiologically linked tuberculosis cases, collected in the Netherlands spanning almost 16 years.Multiple analyses support an average mutation rate of ~0.3 SNPs per genome per year. However, all analyses revealed a very high degree of variation around this mean, making the confirmation of links proposed by epidemiology, and inference of novel links, difficult. Despite this, in some cases, the phylogenetic context of other strains provided evidence supporting the confident exclusion of previously inferred epidemiological links.This in-depth analysis of the molecular clock revealed that it is slow and variable over short time scales, which limits its usefulness in transmission studies. However, the superior resolution of whole genome sequencing can provide the phylogenetic context to allow the confident exclusion of possible transmission events previously inferred via traditional DNA fingerprinting techniques and epidemiological cluster investigation. Despite the slow generation of variation even at the whole genome level we conclude that the investigation of tuberculosis transmission will benefit greatly from routine whole genome sequencing.
| S-EPMC3599118 | biostudies-literature
Project description:Tuberculosis (TB) originating from expatriates that hail from high TB-burden countries is hypothesized to play a role in continued TB transmission in Oman. Here, we used whole-genome sequencing (WGS) to assess national TB transmission dynamics. The annual incidence per 100,000 population per year was calculated for nationals and expatriates. A convenience sample of Mycobacterium tuberculosis (MTB) isolates from 2018 to 2019 was sequenced and analyzed with publicly available TB sequences from Bangladesh, Tanzania, the Philippines, India, and Pakistan. Relatedness was assessed by generating core-genome single nucleotide polymorphism (SNP) distances. The incidence of TB was five cases per 100,000 persons in 2018 and seven cases per 100,000 persons in 2020 (R2 = 0.34, P = 0.60). Incidence among nationals was 3.9 per 100,000 persons in 2018 and 3.5 per 100,000 persons in 2020 (R2 = 0.20, P = 0.70), and incidence among expatriates was 7.2 per 100,000 persons in 2018 and 12.7 per 100,000 persons in 2020 (R2 = 0.74, P = 0.34). Sixty-eight local MTB isolates were sequenced and analyzed with 393 global isolates. Isolates belonged to nine distinct spoligotypes. Two isolates, originating from an expatriate and an Omani national, were grouped into a WGS-based cluster (SNP distance < 12), which was corroborated by an epidemiological investigation. Relatedness of local and global isolates (SNP distance < 100) was also seen. The relatedness between MTB strains in Oman and those in expatriate countries of origin can aid inform TB control policy. Our results provide evidence that WGS can complement epidemiological analysis to achieve the End TB strategy goal in Oman. IMPORTANCE Tuberculosis (TB) incidence in Oman remains above national program control targets. TB transmission originating from expatriates from high TB-burden countries has been hypothesized to play a role. We used whole-genome sequencing (WGS) to assess TB transmission dynamics between expatriates and Omani nationals to inform TB control efforts. Available Mycobacterium tuberculosis isolates from 2018 to 2019 underwent WGS and analysis with publicly available TB sequences from Bangladesh, the Philippines, India, and Pakistan to assess for genetic relatedness. Our analysis revealed evidence of previously unrecognized transmission between an expatriate and an Omani national, which was corroborated by epidemiological investigation. Analysis of local and global isolates revealed evidence of distant relatedness between local and global isolates. Our results provide evidence that WGS can complement classic public health surveillance to inform targeted interventions to achieve the End TB strategy goal in Oman.
| S-EPMC10581073 | biostudies-literature
Project description:BackgroundIn Saudi Arabia, cross-border transmission of multidrug-resistant (MDR) Mycobacterium tuberculosis complex (MTBC) strains might be particularly fostered by high immigration rates. Herein, we aimed to elucidate the transmission dynamics of MDR-MTBC strains and reveal a detailed prediction of all resistance-conferring mutations for the first- and second-line drugs.MethodsWe investigated all MDR-MTBC strains collected between 2015 and 2017 from provincial mycobacteria referral laboratories and compared demographic and clinical parameters to a cohort of non-MDR-TB patients using a whole genome sequencing approach. Clusters were defined based on a maximum strain-to-strain genetic distance of five single-nucleotide polymorphisms (SNPs) as surrogate marker for recent transmission, and then investigated molecular drug-resistance markers (37 genes).ResultsForty-eight (67.6%) MDR-MTBC strains were grouped in 14 different clusters, ranging in size from two to six strains; 22.5% (16/71) of all MDR-MTBC isolates were predicted to be fully resistant to all five first-line drugs, and five strains (7.0%) exhibited fluoroquinolone resistance. Moreover, we revealed the presence of 12 compensatory mutations as well as 26 non-synonymous SNPs in the rpoC gene and non-hotspot region in rpoB, respectively.ConclusionOptimized TB molecular surveillance, diagnosis, and patient management are urgently needed to contain MDR-MTBC transmission and prevent the development of additional drug resistance.
| S-EPMC6237142 | biostudies-literature
Project description:MotivationWhole-genome sequencing (WGS) is increasingly used to aid the understanding of Mycobacterium tuberculosis (MTB) transmission. The epidemiological analysis of tuberculosis based on the WGS technique requires a diverse collection of bioinformatics tools. Effectively using these analysis tools in a scalable and reproducible way can be challenging, especially for non-experts.ResultsHere, we present TransFlow (Transmission Workflow), a user-friendly, fast, efficient and comprehensive WGS-based transmission analysis pipeline. TransFlow combines some state-of-the-art tools to take transmission analysis from raw sequencing data, through quality control, sequence alignment and variant calling, into downstream transmission clustering, transmission network reconstruction and transmission risk factor inference, together with summary statistics and data visualization in a summary report. TransFlow relies on Snakemake and Conda to resolve dependencies among consecutive processing steps and can be easily adapted to any computation environment.Availability and implementationTransFlow is free available at https://github.com/cvn001/transflow.Supplementary informationSupplementary data are available at Bioinformatics online.
| S-EPMC9825751 | biostudies-literature
Project description:BackgroundExtrapulmonary tuberculosis (EPTB) refers to a form of Tuberculosis (TB) where the infection occurs outside the lungs. Despite EPTB being a devastating disease of public health concern, it is frequently overlooked as a public health problem. This study aimed to investigate genetic diversity, identify drug-resistance mutations, and trace ongoing transmission chains.MethodsA cross-sectional study was undertaken on individuals with EPTB in western Ethiopia. In this study, whole-genome sequencing (WGS) was employed to analyze Mycobacterium tuberculosis (MTB) samples obtained from EPTB patients. Out of the 96 genomes initially sequenced, 89 met the required quality standards for genetic diversity, and drug-resistant mutations analysis. The data were processed using robust bioinformatics tools.ResultsOur analysis reveals that the majority (87.64%) of the isolates can be attributed to Lineage-4 (L4), with L4.6.3 and L4.2.2.2 emerging as the predominant sub-lineages, constituting 34.62% and 26.92%, respectively. The overall clustering rate and recent transmission index (RTI) were 30 and 17.24%, respectively. Notably, 7.87% of the isolates demonstrated resistance to at least one anti-TB drug, although multi-drug resistance (MDR) was observed in only 1.12% of the isolates.ConclusionsThe genetic diversity of MTBC strains in western Ethiopia was found to have low inter-lineage diversity, with L4 predominating and exhibiting high intra-lineage diversity. The notably high clustering rate in the region implies a pressing need for enhanced TB infection control measures to effectively disrupt the transmission chain. It's noteworthy that 68.75% of resistance-conferring mutations went undetected by both GeneXpert MTB/RIF and the line probe assay (LPA) in western Ethiopia. The identification of resistance mutations undetected by both GeneXpert and LPA, along with the detection of mixed infections through WGS, emphasizes the value of adopting WGS as a high-resolution approach for TB diagnosis and molecular epidemiological surveillance.
| S-EPMC11341482 | biostudies-literature
Project description:Whole genome sequencing (WGS) of Mycobacterium tuberculosis has been used to trace the transmission of M. tuberculosis, the causative agent of tuberculosis (TB). Previously published studies using WGS were conducted in developed countries with a low TB burden. We sought to evaluate the relative usefulness of traditional VNTR and SNP typing methods, WGS and epidemiological investigations to study the recent transmission of M. tuberculosis in a high TB burden country. We conducted epidemiological investigations of 42 TB patients whose M. tuberculosis isolates were classified into three clusters based on variable-number tandem repeat (VNTR) typing. We applied WGS to 32 (76.2%) of the 42 strains and calculated the pairwise genomic distances between strains within each cluster. Eighteen (56.3%) of the 32 strains had genomic differences ≥100 SNPs with every other strain, suggesting that direct transmission did not likely occurred. Ten strains were grouped into four WGS-based clusters with genomic distances ≤5 SNPs within each cluster, and confirmed epidemiological links were identified in two of these clusters. Our results indicate that WGS provides reliable resolution for tracing the transmission of M. tuberculosis in high TB burden settings. The high resolution of WGS is particularly useful to confirm or exclude the possibility of direct transmission events defined by traditional typing methods.
| S-EPMC4409578 | biostudies-literature
Project description:Tuberculosis (TB) control programs use whole-genome sequencing (WGS) of Mycobacterium tuberculosis (Mtb) for detecting and investigating TB case clusters. Existence of few genomic differences between Mtb isolates might indicate TB cases are the result of recent transmission. However, the variable and sometimes long duration of latent infection, combined with uncertainty in the Mtb mutation rate during latency, can complicate interpretation of WGS results. To estimate the association between infection duration and single nucleotide polymorphism (SNP) accumulation in the Mtb genome, we first analyzed pairwise SNP differences among TB cases from Los Angeles County, California, with strong epidemiologic links. We found that SNP distance alone was insufficient for concluding that cases are linked through recent transmission. Second, we describe a well-characterized cluster of TB cases in California to illustrate the role of genomic data in conclusions regarding recent transmission. Longer presumed latent periods were inconsistently associated with larger SNP differences. Our analyses suggest that WGS alone cannot be used to definitively determine that a case is attributable to recent transmission. Methods for integrating clinical, epidemiologic, and genomic data can guide conclusions regarding the likelihood of recent transmission, providing local public health practitioners with better tools for monitoring and investigating TB transmission.
| S-EPMC8793027 | biostudies-literature