Biomedical subjects

Sebastien Gagneux

Publications and source records attributed to Sebastien Gagneux.

9 recordsLinked to original sources

PubMed2025

Mycobacterium tuberculosis complex Lineage 1: A neglected cause of tuberculosis.

The Mycobacterium tuberculosis complex (MTBC) phylogenetic lineages 1-4 (L1-L4) are the main causes of human tuberculosis (TB). Until now, most of the focus in the TB field has been on MTBC L2 and L4, as these two lineages are geographically widespread and have been repeatedly associated with multidrug resistance. By comparison, MTBC L1 has received little attention, partially because of its restricted geographical range that mainly includes low- to middle-income countries in South and Southeast Asia, and East Africa. However, recent estimates indicate that MTBC L1 is in fact the most common cause of human TB in terms of absolute numbers of TB patients, particularly among several high TB burden countries. As more L1 strains are being sampled in L1-endemic countries, the high genetic diversity of this geographically restricted MTBC lineage is slowly uncovered. This discovery has also impacted L1 nomenclature, which has been modified as new distinct L1 clades were identified. In parallel to the genomic discoveries ushered by progress in whole genome sequencing, clinical researchers have also studied several phenotypes that better describe L1 TB disease. L1 strains have been shown to have increased vulnerability to oxidative stress, which was associated with decreased virulence in animal and in vitro models. L1 infection also shows possible association with extrapulmonary TB and asymptomatic TB. However, despite belonging to the same lineage, L1 strains display phenotypic diversity that can be attributed to high within-lineage genetic diversity and possibly the interaction of different L1 genotypes with different human host genotypes. Among the clinical phenotypes that show heterogeneity are bacterial factors, immune profiles, and clinical virulence. The traditional view regarding the reduced transmissibility in L1 is now being challenged by new data indicating that L1 may be as transmissible as L2 or L4. Lastly, although historically referred to as being negatively associated with drug resistance, there is indication that the contribution of L1 to TB drug resistance is significant and that it may evolve drug resistance in ways distinct from those of other MTBC lineages.

Mycobacterium tuberculosis↗

PubMed2025

Genome-to-genome analysis reveals associations between human and mycobacterial genetic variation in tuberculosis patients from Tanzania.

The risk and prognosis of tuberculosis (TB) are influenced by a complex interplay between human and bacterial genetic factors. While previous genomic studies have largely examined human and bacterial genomes separately, we adopted an integrated approach to uncover host-pathogen interactions. We leveraged paired human and Mycobacterium tuberculosis (M.tb) genomic data from 1000 adult TB patients from Tanzania and used a "genome-to-genome" approach to search for associations between human and M.tb genetic variants and to identify interacting genetic loci. Our analyses revealed two significant host-pathogen genetic associations. The first significant association (p = 4.7e-11) links a human intronic variant in PRDM15 (rs12151990), a gene involved in apoptosis regulation, with an M.tb variant in Rv2348c (I101M), which encodes a T cell-stimulating antigen. The second significant association (p = 6.3e-11) connects a human intergenic variant near TIMM21 and FBXO15 (rs75769176) - also associated with TB severity (p = 0.04) - with an M.tb variant in FixA (T67M). While FBXO15 is involved in the regulation of antigen processing and TIMM21 affects mitochondrial function, FixA's role remains undefined due to limited functional characterization. Additionally, we observed that a group of M.tb T cell epitope variants were significantly associated with HLA-DRB1 variation, suggesting that, despite their rarity, certain epitopes may still be subjected to immune selective pressure. Together, these findings identify previously unknown sites of genomic conflicts between humans and M.tb, advancing our understanding of how this pathogen evades selection pressure and persist in human populations.

Humans↗

PubMed2010

Human T cell epitopes of Mycobacterium tuberculosis are evolutionarily hyperconserved.

Mycobacterium tuberculosis is an obligate human pathogen capable of persisting in individual hosts for decades. We sequenced the genomes of 21 strains representative of the global diversity and six major lineages of the M. tuberculosis complex (MTBC) at 40- to 90-fold coverage using Illumina next-generation DNA sequencing. We constructed a genome-wide phylogeny based on these genome sequences. Comparative analyses of the sequences showed, as expected, that essential genes in MTBC were more evolutionarily conserved than nonessential genes. Notably, however, most of the 491 experimentally confirmed human T cell epitopes showed little sequence variation and had a lower ratio of nonsynonymous to synonymous changes than seen in essential and nonessential genes. We confirmed these findings in an additional data set consisting of 16 antigens in 99 MTBC strains. These findings are consistent with strong purifying selection acting on these epitopes, implying that MTBC might benefit from recognition by human T cells.

Antigens, Bacterial↗

PubMed2006

The competitive cost of antibiotic resistance in Mycobacterium tuberculosis.

Mathematical models predict that the future of the multidrug-resistant tuberculosis epidemic will depend on the fitness cost of drug resistance. We show that in laboratory-derived mutants of Mycobacterium tuberculosis, rifampin resistance is universally associated with a competitive fitness cost and that this cost is determined by the specific resistance mutation and strain genetic background. In contrast, we demonstrate that prolonged patient treatment can result in multidrug-resistant strains with no fitness defect and that strains with low- or no-cost resistance mutations are also the most frequent among clinical isolates.

Amino Acid Substitution↗

PubMed2006

Mycobacterium africanum elicits an attenuated T cell response to early secreted antigenic target, 6 kDa, in patients with tuberculosis and their household contacts.

BACKGROUND: Mycobacterium africanum, a member of the M. tuberculosis complex that is infrequently found outside of western Africa, is the cause of up to half of the tuberculosis cases there. METHODS: We genotyped mycobacterial isolates obtained from a study of patients with tuberculosis and their household contacts and compared T cell responses and tuberculin skin test results by infecting genotype. RESULTS: The T cell response to early secreted antigenic target, 6 kDa (ESAT-6), was attenuated in patients with tuberculosis (odds ratio [OR], 0.41 [95% confidence interval {CI}, 0.19-0.89]; P = .024) and household contacts (OR, 0.56 [95% CI, 0.38-0.83]; P = .004) infected with M. africanum, compared with the response in those infected with M. tuberculosis. In these same groups, responses to culture filtrate protein, 10 kDa (CFP-10), were nonsignificantly attenuated (P = .22 and P = .16, respectively), as were tuberculin skin test results (P = .30 and P = .46, respectively). Sequencing of region of difference 1 of M. africanum revealed that Rv3879c is a pseudogene in M. africanum; however, this finding does not provide an obvious mechanism for the attenuated ESAT-6 response. CONCLUSIONS: This is the first evidence, to our knowledge, that strain differences affect interferon- gamma -based T cell responses. Our findings highlight the need to test new diagnostic candidates against different strains of mycobacteria. Integrating additional immunologic and genomic comparisons of M. tuberculosis and M. africanum into further studies may provide fundamental insights into the interactions between humans and mycobacteria.

Adolescent↗

PubMed2006

Variable host-pathogen compatibility in Mycobacterium tuberculosis.

Mycobacterium tuberculosis remains a major cause of morbidity and mortality worldwide. Studies have reported human pathogens to have geographically structured population genetics, some of which have been linked to ancient human migrations. However, no study has addressed the potential evolutionary consequences of such longstanding human-pathogen associations. Here, we demonstrate that the global population structure of M. tuberculosis is defined by six phylogeographical lineages, each associated with specific, sympatric human populations. In an urban cosmopolitan environment, mycobacterial lineages were much more likely to spread in sympatric than in allopatric patient populations. Tuberculosis cases that did occur in allopatric hosts disproportionately involved high-risk individuals with impaired host resistance. These observations suggest that mycobacterial lineages are adapted to particular human populations. If confirmed, our findings have important implications for tuberculosis control and vaccine development.

Adaptation, Physiological↗

PubMed2005

Genomic deletions classify the Beijing/W strains as a distinct genetic lineage of Mycobacterium tuberculosis.

Beijing/W strains of Mycobacterium tuberculosis are geographically widespread and hypervirulent. To enhance our understanding of their origin and evolution, we sought phylogenetically informative large sequence polymorphisms (LSPs) within the Beijing/W family. Comparative whole-genome hybridization of Beijing/W strains revealed 21 LSPs, 7 of which were previously unreported. We show that some of these LSPs are unique event polymorphisms that can be used to define and subdivide the Beijing/W family. One LSP (RD105) was seen in all Beijing/W strains and thus serves as a useful marker for the identification of this family of strains. Additional LSPs (RD142, RD150, and RD181) further divided this family into four monophyletic subgroups, demonstrating a deeper population structure than previously appreciated. All Beijing/W strains were also observed to have an intact pks15/1 gene that is involved in the biosynthesis of a phenolic glycolipid, a putative virulence factor. A simple PCR assay using these Beijing/W strain-defining deletions will facilitate molecular epidemiological studies and may assist in the identification of the molecular basis of phenotypes associated with this important lineage of M. tuberculosis.

Base Sequence↗

PubMed2005

Does resistance to pyrazinamide accurately indicate the presence of Mycobacterium bovis?

Mycobacterium bovis is best identified by screening those isolates of the Mycobacterium tuberculosis complex that have any pyrazinamide (PZA) resistance, using a confirmatory test such as spoligotyping, biochemical testing, or genomic deletion analysis. The sensitivity for detection of M. bovis is lowered to 82% when only PZA-monoresistant isolates are screened.

Adult↗

PubMed2004

Genomic analysis distinguishes Mycobacterium africanum.

Mycobacterium africanum is thought to comprise a unique species within the Mycobacterium tuberculosis complex. M. africanum has traditionally been identified by phenotypic criteria, occupying an intermediate position between M. tuberculosis and M. bovis according to biochemical characteristics. Although M. africanum isolates present near-identical sequence homology to other species of the M. tuberculosis complex, several studies have uncovered large genomic regions variably deleted from certain M. africanum isolates. To further investigate the genomic characteristics of organisms characterized as M. africanum, the DNA content of 12 isolates was interrogated by using Affymetrix GeneChip. Analysis revealed genomic regions of M. tuberculosis deleted from all isolates of putative diagnostic and biological consequence. The distribution of deleted sequences suggests that M. africanum subtype II isolates are situated among strains of "modern" M. tuberculosis. In contrast, other M. africanum isolates (subtype I) constitute two distinct evolutionary branches within the M. tuberculosis complex. To test for an association between deleted sequences and biochemical attributes used for speciation, a phenotypically diverse panel of "M. africanum-like" isolates from Guinea-Bissau was tested for these deletions. These isolates clustered together within one of the M. africanum subtype I branches, irrespective of phenotype. These results indicate that convergent biochemical profiles can be independently obtained for M. tuberculosis complex members, challenging the traditional approach to M. tuberculosis complex speciation. Furthermore, the genomic results suggest a rational framework for defining M. africanum and provide tools to accurately assess its prevalence in clinical specimens.

Genome, Bacterial↗