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TbD1 deletion as a driver of the evolutionary success of modern epidemic Mycobacterium tuberculosis lineages.

ABSTRACT: Mycobacterium tuberculosis (Mtb) strains are classified into different phylogenetic lineages (L), three of which (L2/L3/L4) emerged from a common progenitor after the loss of the MmpS6/MmpL6-encoding Mtb-specific deletion 1 region (TbD1). These TbD1-deleted "modern" lineages are responsible for globally-spread tuberculosis epidemics, whereas TbD1-intact "ancestral" lineages tend to be restricted to specific geographical areas, such as South India and South East Asia (L1) or East Africa (L7). By constructing and characterizing a panel of recombinant TbD1-knock-in and knock-out strains and comparison with clinical isolates, here we show that deletion of TbD1 confers to Mtb a significant increase in resistance to oxidative stress and hypoxia, which correlates with enhanced virulence in selected cellular, guinea pig and C3HeB/FeJ mouse infection models, the latter two mirroring in part the development of hypoxic granulomas in human disease progression. Our results suggest that loss of TbD1 at the origin of the L2/L3/L4 Mtb lineages was a key driver for their global epidemic spread and outstanding evolutionary success.

SUBMITTER: Bottai D

PROVIDER: S-EPMC7000671 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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TbD1 deletion as a driver of the evolutionary success of modern epidemic Mycobacterium tuberculosis lineages.

Bottai Daria D Frigui Wafa W Sayes Fadel F Di Luca Mariagrazia M Spadoni Dalila D Pawlik Alexandre A Zoppo Marina M Orgeur Mickael M Khanna Varun V Hardy David D Mangenot Sophie S Barbe Valerie V Medigue Claudine C Ma Laurence L Bouchier Christiane C Tavanti Arianna A Larrouy-Maumus Gerald G Brosch Roland R

Nature communications 20200204 1

Mycobacterium tuberculosis (Mtb) strains are classified into different phylogenetic lineages (L), three of which (L2/L3/L4) emerged from a common progenitor after the loss of the MmpS6/MmpL6-encoding Mtb-specific deletion 1 region (TbD1). These TbD1-deleted "modern" lineages are responsible for globally-spread tuberculosis epidemics, whereas TbD1-intact "ancestral" lineages tend to be restricted to specific geographical areas, such as South India and South East Asia (L1) or East Africa (L7). By ...[more]

PMID: 32019932

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Project description:BackgroundLineage distribution of Mycobacterium tuberculosis (Mtb) isolates is strongly associated with geographically distinct human populations, and its transmission can be further impacted by the bacterial genome. However, the epidemic success of Mtb isolates at an individual level was unknown in eastern China. Knowledge regarding the emergence and transmission of Mtb isolates as well as relevant factors may offer a new solution to curb the spread of the disease. Thus, this study aims to reveal the evolution and epidemic success of Mtb isolates in eastern China.ResultsOf initial 1040 isolates, 997 were retained after removing duplicates and those with insufficient sequencing depth. Of the final samples, 733 (73.52%) were from Zhejiang Province, and 264 (26.48%) were from Shanghai City. Lineage 2 and lineage 4 accounted for 80.44% and 19.56%, with common ancestors dating around 7017 years ago and 6882 years ago, respectively. Sub-lineage L2.2 (80.34%) contributed the majority of total isolates, followed by L4.4 (8.93%) and L4.5 (8.43%). Additionally, 51 (5.12%) isolates were identified to be multidrug-resistant (MDR), of which 21 (29.17%) were pre-extensively drug-resistant (pre-XDR). One clade harboring katG S315T mutation may date back to 65 years ago and subsequently acquired mutations conferring resistance to another five antibiotic drugs. The prevalence of compensatory mutation was the highest in pre-XDR isolates (76.19%), followed by MDR isolates (47.06%) and other drug-resistant isolates (20.60%). Time-scaled haplotypic density analyses suggested comparable success indices between lineage 2 and lineage 4 (P = 0.306), and drug resistance did not significantly promote the transmission of Mtb isolates (P = 0.340). But for pre-XDR isolates, we found a higher success index in those with compensatory mutations (P = 0.025). Mutations under positive selection were found in genes associated with resistance to second-line injectables (whiB6) and drug tolerance (prpR) in both lineage 2 and lineage 4.ConclusionsOur study demonstrates the population expansion of lineage 2 and lineage 4 in eastern China, with comparable transmission capacity, while accumulation of resistance mutations does not necessarily facilitate the success of Mtb isolates. Compensatory mutations usually accompany drug resistance and significantly contribute to the epidemiological transmission of pre-XDR strains. Prospective molecular surveillance is required to further monitor the emergence and spread of pre-XDR/XDR strains in eastern China.

Project description:Resistance to drugs used to treat tuberculosis disease (TB) continues to remain a public health burden, with missense point mutations in the underlying Mycobacterium tuberculosis bacteria described for nearly all anti-TB drugs. The post-genomics era along with advances in computational and structural biology provide opportunities to understand the interrelationships between the genetic basis and the structural consequences of M. tuberculosis mutations linked to drug resistance. Pyrazinamide (PZA) is a crucial first line antibiotic currently used in TB treatment regimens. The mutational promiscuity exhibited by the pncA gene (target for PZA) necessitates computational approaches to investigate the genetic and structural basis for PZA resistance development. We analysed 424 missense point mutations linked to PZA resistance derived from ∼35K M. tuberculosis clinical isolates sourced globally, which comprised the four main M. tuberculosis lineages (Lineage 1-4). Mutations were annotated to reflect their association with PZA resistance. Genomic measures (minor allele frequency and odds ratio), structural features (surface area, residue depth and hydrophobicity) and biophysical effects (change in stability and ligand affinity) of point mutations on pncA protein stability and ligand affinity were assessed. Missense point mutations within pncA were distributed throughout the gene, with the majority (>80%) of mutations with a destabilising effect on protomer stability and on ligand affinity. Active site residues involved in PZA binding were associated with multiple point mutations highlighting mutational diversity due to selection pressures at these functionally important sites. There were weak associations between genomic measures and biophysical effect of mutations. However, mutations associated with PZA resistance showed statistically significant differences between structural features (surface area and residue depth), but not hydrophobicity score for mutational sites. Most interestingly M. tuberculosis lineage 1 (ancient lineage) exhibited a distinct protein stability profile for mutations associated with PZA resistance, compared to modern lineages.

Dataset Information

TbD1 deletion as a driver of the evolutionary success of modern epidemic Mycobacterium tuberculosis lineages.

Publications

TbD1 deletion as a driver of the evolutionary success of modern epidemic Mycobacterium tuberculosis lineages.

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