Comparative genomics shows differences in the electron transport and carbon metabolic pathways of Mycobacterium africanum relative to Mycobacterium tuberculosis and suggests an adaptation to low oxygen tension

Ofori-Anyinam, Boatema; Riley, Abi Janet; Jobarteh, Tijan; Gitteh, Ensa; Sarr, Binta; Faal-Jawara, Tutty Isatou; Rigouts, Leen; Senghore, Madikay; Kehinde, Aderemi; Onyejepu, Nneka; Antonio, Martín; Jong, Bouke C. de; Gehre, Florian; Meehan, Conor J.

doi:10.1016/j.tube.2020.101899

Cited by 18 publications

(16 citation statements)

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“…L5 and L6 differ substantially from other MTBC lineages with respect to in vitro growth and metabolism [20–25], and in various molecular features relevant for patient diagnosis, such as a non-synonymous mutation in the MPT64 antigen [26] and reduced T cell response to ESAT6 [27]. Mycobacterial genetic determinants are also implicated in virulence and immunogenicity in M.…”

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confidence: 99%

Phylogenomics of Mycobacterium africanum reveals a new lineage and a complex evolutionary history

et al. 2021

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Human tuberculosis (TB) is caused by members of the Mycobacterium tuberculosis complex (MTBC). The MTBC comprises several human-adapted lineages known as M. tuberculosis sensu stricto, as well as two lineages (L5 and L6) traditionally referred to as Mycobacterium africanum . Strains of L5 and L6 are largely limited to West Africa for reasons unknown, and little is known of their genomic diversity, phylogeography and evolution. Here, we analysed the genomes of 350 L5 and 320 L6 strains, isolated from patients from 21 African countries, plus 5 related genomes that had not been classified into any of the known MTBC lineages. Our population genomic and phylogeographical analyses showed that the unclassified genomes belonged to a new group that we propose to name MTBC lineage 9 (L9). While the most likely ancestral distribution of L9 was predicted to be East Africa, the most likely ancestral distribution for both L5 and L6 was the Eastern part of West Africa. Moreover, we found important differences between L5 and L6 strains with respect to their phylogeographical substructure and genetic diversity. Finally, we could not confirm the previous association of drug-resistance markers with lineage and sublineages. Instead, our results indicate that the association of drug resistance with lineage is most likely driven by sample bias or geography. In conclusion, our study sheds new light onto the genomic diversity and evolutionary history of M. africanum , and highlights the need to consider the particularities of each MTBC lineage for understanding the ecology and epidemiology of TB in Africa and globally.

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Section: Introductionmentioning

confidence: 99%

Phylogenomics of Mycobacterium africanum reveals a new lineage and a complex evolutionary history

et al. 2021

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“…africanum and M . bovis which impairs the activity of pyruvate kinase in the metabolism of carbohydrates [ 44 , 47 , 55 ]. Another SNP, R179S, in the eno gene was found to be associated with only L6 which could contribute to the more impaired utilization of glycerol among L6 strains [ 55 ].…”

Section: Discussionmentioning

confidence: 99%

Genotypic and phenotypic diversity of Mycobacterium tuberculosis complex genotypes prevalent in West Africa

et al. 2021

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Findings from previous comparative genomics studies of the Mycobacterium tuberculosis complex (MTBC) suggest genomic variation among the genotypes may have phenotypic implications. We investigated the diversity in the phenotypic profiles of the main prevalent MTBC genotypes in West Africa. Thirty-six whole genome sequenced drug susceptible MTBC isolates belonging to lineages 4, 5 and 6 were included in this study. The isolates were phenotypically characterized for urease activity, tween hydrolysis, Thiophen-2-Carboxylic Acid Hydrazide (TCH) susceptibility, nitric oxide production, and growth rate in both liquid (7H9) and solid media (7H11 and Löwenstein–Jensen (L-J)). Lineage 4 isolates showed the highest growth rate in both liquid (p = 0.0003) and on solid (L-J) media supplemented with glycerol (p<0.001) or pyruvate (p = 0.005). L6 isolates optimally utilized pyruvate compared to glycerol (p<0.001), whereas L5 isolates grew similarly on both media (p = 0.05). Lineage 4 isolates showed the lowest average time to positivity (TTP) (p = 0.01; Average TTP: L4 = 15days, L5 = 16.7days, L6 = 29.7days) and the highest logCFU/mL (p = 0.04; average logCFU/mL L4 = 5.9, L5 = 5.0, L6 = 4.4) on 7H11 supplemented with glycerol, but there was no significant difference in growth on 7H11 supplemented with pyruvate (p = 0.23). The highest release of nitrite was recorded for L5 isolates, followed by L4 and L6 isolates. However, the reverse was observed in the urease activity for the lineages. All isolates tested were resistant to TCH except for one L6 isolate. Comparative genomic analyses revealed several mutations that might explain the diverse phenotypic profiles of these isolates. Our findings showed significant phenotypic diversity among the MTBC lineages used for this study.

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“…Mutations in genes essential for growth in culture were identified for L6 strains [30], yet for L5 strains the reasons for the difficulty in growth remain unclear. L6 strains and those of the closely related animal strains/lineages such as Mycobacterium bovis are reported to be less virulent in humans than those from other human-adapted MTBC lineages in populationbased studies [20,31,32] and in genome studies of mutations in virulence regulation genes/systems [33,34]. Infection with an L6 strain progresses slowly to TB disease, and is associated with impaired immunity in some settings but not all (e.g.…”

Section: Introductionmentioning

confidence: 99%

Mycobacterium tuberculosis complex lineage 5 exhibits high levels of within-lineage genomic diversity and differing gene content compared to the type strain H37Rv

et al. 2021

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Pathogens of the Mycobacterium tuberculosis complex (MTBC) are considered to be monomorphic, with little gene content variation between strains. Nevertheless, several genotypic and phenotypic factors separate strains of the different MTBC lineages (L), especially L5 and L6 (traditionally termed Mycobacterium africanum ) strains, from each other. However, this genome variability and gene content, especially of L5 strains, has not been fully explored and may be important for pathobiology and current approaches for genomic analysis of MTBC strains, including transmission studies. By comparing the genomes of 355 L5 clinical strains (including 3 complete genomes and 352 Illumina whole-genome sequenced isolates) to each other and to H37Rv, we identified multiple genes that were differentially present or absent between H37Rv and L5 strains. Additionally, considerable gene content variability was found across L5 strains, including a split in the L5.3 sub-lineage into L5.3.1 and L5.3.2. These gene content differences had a small knock-on effect on transmission cluster estimation, with clustering rates influenced by the selected reference genome, and with potential overestimation of recent transmission when using H37Rv as the reference genome. We conclude that full capture of the gene diversity, especially high-resolution outbreak analysis, requires a variation of the single H37Rv-centric reference genome mapping approach currently used in most whole-genome sequencing data analysis pipelines. Moreover, the high within-lineage gene content variability suggests that the pan-genome of M. tuberculosis is at least several kilobases larger than previously thought, implying that a concatenated or reference-free genome assembly (de novo) approach may be needed for particular questions.

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Comparative genomics shows differences in the electron transport and carbon metabolic pathways of Mycobacterium africanum relative to Mycobacterium tuberculosis and suggests an adaptation to low oxygen tension

Cited by 18 publications

References 109 publications

Phylogenomics of Mycobacterium africanum reveals a new lineage and a complex evolutionary history

Phylogenomics of Mycobacterium africanum reveals a new lineage and a complex evolutionary history

Genotypic and phenotypic diversity of Mycobacterium tuberculosis complex genotypes prevalent in West Africa

Mycobacterium tuberculosis complex lineage 5 exhibits high levels of within-lineage genomic diversity and differing gene content compared to the type strain H37Rv

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