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Human macrophage responses to clinical isolates from the Mycobacterium tuberculosis complex discriminate between ancient and modern lineages.

ABSTRACT: The aim of the present study was to determine whether there is a correlation between phylogenetic relationship and inflammatory response amongst a panel of clinical isolates representative of the global diversity of the human Mycobacterium tuberculosis Complex (MTBC). Measurement of cytokines from infected human peripheral blood monocyte-derived macrophages revealed a wide variation in the response to different strains. The same pattern of high or low response to individual strains was observed for different pro-inflammatory cytokines and chemokines, and was conserved across multiple human donors. Although each major phylogenetic lineage of MTBC included strains inducing a range of cytokine responses, we found that overall inflammatory phenotypes differed significantly across lineages. In particular, comparison of evolutionarily modern lineages demonstrated a significant skewing towards lower early inflammatory response. The differential response to ancient and modern lineages observed using GM-CSF derived macrophages was also observed in autologous monocyte-derived dendritic cells and murine bone marrow-derived macrophages, but not in human unfractionated peripheral blood mononuclear cells. We hypothesize that the reduced immune responses to modern lineages contribute to more rapid disease progression and transmission, which might be a selective advantage in the context of expanding human populations. In addition to the lineage effects, the large strain-to-strain variation in innate immune responses elicited by MTBC will need to be considered in tuberculosis vaccine development.

SUBMITTER: Portevin D

PROVIDER: S-EPMC3048359 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Human macrophage responses to clinical isolates from the Mycobacterium tuberculosis complex discriminate between ancient and modern lineages.

Portevin Damien D Gagneux Sébastien S Comas Iñaki I Young Douglas D

PLoS pathogens 20110303 3

The aim of the present study was to determine whether there is a correlation between phylogenetic relationship and inflammatory response amongst a panel of clinical isolates representative of the global diversity of the human Mycobacterium tuberculosis Complex (MTBC). Measurement of cytokines from infected human peripheral blood monocyte-derived macrophages revealed a wide variation in the response to different strains. The same pattern of high or low response to individual strains was observed ...[more]

PMID: 21408618

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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.

Project description:Current knowledge on resistance-conferring determinants in Mycobacterium tuberculosis is biased toward globally dominant lineages 2 and 4. In contrast, lineages 1 and 3 are predominant in India. In this study, we performed whole-genome sequencing of 498 MDR M. tuberculosis isolates from India to determine the prevalence of drug resistance mutations and to understand the genomic diversity. A retrospective collection of 498 M. tuberculosis isolates submitted to the National Institute for Research in Tuberculosis for phenotypic susceptibility testing between 2014 to 2016 were sequenced. Genotypic resistance prediction was performed using known resistance-conferring determinants. Genotypic and phenotypic results for 12 antituberculosis drugs were compared, and sequence data were explored to characterize lineages and their association with drug resistance. Four lineages were identified although lineage 1 predominated (43%). The sensitivity of prediction for isoniazid and rifampicin was 92% and 98%, respectively. We observed lineage-specific variations in the proportion of isolates with resistance-conferring mutations, with drug resistance more common in lineages 2 and 3. Disputed mutations (codons 430, 435, 445, and 452) in the rpoB gene were more common in isolates other than lineage 2. Phylogenetic analysis and pairwise SNP difference revealed high genetic relatedness of lineage 2 isolates. WGS based resistance prediction has huge potential, but knowledge of regional and national diversity is essential to achieve high accuracy for resistance prediction. IMPORTANCE Current knowledge on resistance-conferring determinants in Mycobacterium tuberculosis is biased toward globally dominant lineages 2 and 4. In contrast, lineages 1 and 3 are predominant in India. We performed whole-genome sequencing of 498 MDR M. tuberculosis isolates from India to determine the prevalence of drug resistance mutations and to understand genomic diversity. Four lineages were identified although lineage 1 predominated (43%). The sensitivity of prediction for isoniazid and rifampicin was 92% and 98%, respectively. We observed lineage-specific variations in the proportion of isolates with resistance-conferring mutations, with drug resistance more common in lineages 2 and 3. Disputed mutations (codons 430, 435, 445, and 452) in the rpoB gene were more common in isolates other than lineage 2. Phylogenetic analysis and pairwise SNP difference revealed high genetic relatedness of lineage 2 isolates. WGS based resistance prediction has huge potential, but knowledge of regional and national diversity is essential to achieve high accuracy for resistance prediction.

Dataset Information

Human macrophage responses to clinical isolates from the Mycobacterium tuberculosis complex discriminate between ancient and modern lineages.

Publications

Human macrophage responses to clinical isolates from the Mycobacterium tuberculosis complex discriminate between ancient and modern lineages.

Similar Datasets

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