ArticlePLoS pathogens2021
Rifampicin exposure reveals within-host Mycobacterium tuberculosis diversity in patients with delayed culture conversion.
Article in PLoS pathogens, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed.
- High rifampicin peak plasma concentrations accelerate the slow phase of bacterial decline in tuberculosis patients: Evidence for heteroresistance.PLoS computational biology · 2023Article
- A road map for in vivo evolution experiments with blood-borne parasitic microbes.Molecular ecology resources · 2022Review
- Opti-4TB: A protocol for a prospective cohort study evaluating the performance of new biomarkers for active tuberculosis outcome prediction.Frontiers in medicine · 2022Article
- The evolving biology ofFrontiers in cellular and infection microbiology · 2022Review
- In-Depth Immunophenotyping With Mass Cytometry During TB Treatment Reveals New T-Cell Subsets Associated With Culture Conversion.Frontiers in immunology · 2022Article
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Authors and funding
14 authors.
Funding
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Abstract
Mycobacterium tuberculosis (Mtb) genetic micro-diversity in clinical isolates may underline mycobacterial adaptation to tuberculosis (TB) infection and provide insights to anti-TB treatment response and emergence of resistance. Herein we followed within-host evolution of Mtb clinical isolates in two cohorts of TB patients, either with delayed Mtb culture conversion (> 2 months), or with fast culture conversion (< 2 months). We captured the genetic diversity of Mtb isolates obtained in each patient, by focusing on minor variants detected as unfixed single nucleotide polymorphisms (SNPs). To unmask antibiotic tolerant sub-populations, we exposed these isolates to rifampicin (RIF) prior to whole genome sequencing (WGS) analysis. Thanks to WGS, we detected at least 1 unfixed SNP within the Mtb isolates for 9/15 patients with delayed culture conversion, and non-synonymous (ns) SNPs for 8/15 patients. Furthermore, RIF exposure revealed 9 additional unfixed nsSNP from 6/15 isolates unlinked to drug resistance. By contrast, in the fast culture conversion cohort, RIF exposure only revealed 2 unfixed nsSNP from 2/20 patients. To better understand the dynamics of Mtb micro-diversity, we investigated the variant composition of a persistent Mtb clinical isolate before and after controlled stress experiments mimicking the course of TB disease. A minor variant, featuring a particular mycocerosates profile, became enriched during both RIF exposure and macrophage infection. The variant was associated with drug tolerance and intracellular persistence, consistent with the pharmacological modeling predicting increased risk of treatment failure. A thorough study of such variants not necessarily linked to canonical drug-resistance, but which are prone to promote anti-TB drug tolerance, may be crucial to prevent the subsequent emergence of resistance. Taken together, the present findings support the further exploration of Mtb micro-diversity as a promising tool to detect patients at risk of poorly responding to anti-TB treatment, ultimately allowing improved and personalized TB management.
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