Dataset Information

Unexpected Genomic and Phenotypic Diversity of Mycobacterium africanum Lineage 5 Affects Drug Resistance, Protein Secretion, and Immunogenicity.

ABSTRACT: Mycobacterium africanum consists of Lineages L5 and L6 of the Mycobacterium tuberculosis complex (MTBC) and causes human tuberculosis in specific regions of Western Africa, but is generally not transmitted in other parts of the world. Since M. africanum is evolutionarily closely placed between the globally dispersed Mycobacterium tuberculosis and animal-adapted MTBC-members, these lineages provide valuable insight into M. tuberculosis evolution. Here, we have collected 15 M. africanum L5 strains isolated in France over 4 decades. Illumina sequencing and phylogenomic analysis revealed a previously underappreciated diversity within L5, which consists of distinct sublineages. L5 strains caused relatively high levels of extrapulmonary tuberculosis and included multi- and extensively drug-resistant isolates, especially in the newly defined sublineage L5.2. The specific L5 sublineages also exhibit distinct phenotypic characteristics related to in vitro growth, protein secretion and in vivo immunogenicity. In particular, we identified a PE_PGRS and PPE-MPTR secretion defect specific for sublineage L5.2, which was independent of PPE38. Furthermore, L5 isolates were able to efficiently secrete and induce immune responses against ESX-1 substrates contrary to previous predictions. These phenotypes of Type VII protein secretion and immunogenicity provide valuable information to better link genome sequences to phenotypic traits and thereby understand the evolution of the MTBC.

SUBMITTER: Ates LS

PROVIDER: S-EPMC6071665 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Unexpected Genomic and Phenotypic Diversity of Mycobacterium africanum Lineage 5 Affects Drug Resistance, Protein Secretion, and Immunogenicity.

Ates Louis S LS Dippenaar Anzaan A Sayes Fadel F Pawlik Alexandre A Bouchier Christiane C Ma Laurence L Warren Robin M RM Sougakoff Wladimir W Majlessi Laleh L van Heijst Jeroen W J JWJ Brossier Florence F Brosch Roland R

Genome biology and evolution 20180801 8

Mycobacterium africanum consists of Lineages L5 and L6 of the Mycobacterium tuberculosis complex (MTBC) and causes human tuberculosis in specific regions of Western Africa, but is generally not transmitted in other parts of the world. Since M. africanum is evolutionarily closely placed between the globally dispersed Mycobacterium tuberculosis and animal-adapted MTBC-members, these lineages provide valuable insight into M. tuberculosis evolution. Here, we have collected 15 M. africanum L5 strains ...[more]

PMID: 30010947

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Project description:A total of two lineages of Mycobacterium tuberculosis var. africanum (Maf), L5 and L6, which are members of the Mycobacterium tuberculosis complex (MTBC), are responsible for causing tuberculosis in West Africa. Regions of difference (RDs) are usually used for delineation of MTBC. With increased data availability, single nucleotide polymorphisms (SNPs) promise to provide better resolution. Publicly available 380 Maf samples were analyzed for identification of "core-cluster-specific-SNPs," while additional 270 samples were used for validation. RD-based methods were used for lineage-assignment, wherein 31 samples remained unidentified. The genetic diversity of Maf was estimated based on genome-wide SNPs using phylogeny and population genomics approaches. Lineage-based clustering (L5 and L6) was observed in the whole genome phylogeny with distinct sub-clusters. Population stratification using both model-based and de novo approaches supported the same observations. L6 was further delineated into three sub-lineages (L6.1-L6.3), whereas L5 was grouped as L5.1 and L5.2 based on the occurrence of RD711. L5.1 and L5.2 were further divided into two (L5.1.1 and L5.1.2) and four (L5.2.1-L5.2.4) sub-clusters, respectively. Unassigned samples could be assigned to definite lineages/sub-lineages based on clustering observed in phylogeny along with high-confidence posterior membership scores obtained during population stratification. Based on the (sub)-clusters delineated, "core-cluster-specific-SNPs" were derived. Synonymous SNPs (137 in L5 and 128 in L6) were identified as biomarkers and used for validation. Few of the cluster-specific missense variants in L5 and L6 belong to the central carbohydrate metabolism pathway which include His6Tyr (Rv0946c), Glu255Ala (Rv1131), Ala309Gly (Rv2454c), Val425Ala and Ser112Ala (Rv1127c), Gly198Ala (Rv3293) and Ile137Val (Rv0363c), Thr421Ala (Rv0896), Arg442His (Rv1248c), Thr218Ile (Rv1122), and Ser381Leu (Rv1449c), hinting at the differential growth attenuation. Genes harboring multiple (sub)-lineage-specific "core-cluster" SNPs such as Lys117Asn, Val447Met, and Ala455Val (Rv0066c; icd2) present across L6, L6.1, and L5, respectively, hinting at the association of these SNPs with selective advantage or host-adaptation. Cluster-specific SNPs serve as additional markers along with RD-regions for Maf delineation. The identified SNPs have the potential to provide insights into the genotype-phenotype correlation and clues for endemicity of Maf in the African population.

Dataset Information

Unexpected Genomic and Phenotypic Diversity of Mycobacterium africanum Lineage 5 Affects Drug Resistance, Protein Secretion, and Immunogenicity.

Publications

Unexpected Genomic and Phenotypic Diversity of Mycobacterium africanum Lineage 5 Affects Drug Resistance, Protein Secretion, and Immunogenicity.

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