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In-host population dynamics of Mycobacterium tuberculosis complex during active disease.

ABSTRACT: Tuberculosis (TB) is a leading cause of death globally. Understanding the population dynamics of TB's causative agent Mycobacterium tuberculosis complex (Mtbc) in-host is vital for understanding the efficacy of antibiotic treatment. We use longitudinally collected clinical Mtbc isolates that underwent Whole-Genome Sequencing from the sputa of 200 patients to investigate Mtbc diversity during the course of active TB disease after excluding 107 cases suspected of reinfection, mixed infection or contamination. Of the 178/200 patients with persistent clonal infection >2 months, 27 developed new resistance mutations between sampling with 20/27 occurring in patients with pre-existing resistance. Low abundance resistance variants at a purity of ?19% in the first isolate predict fixation in the subsequent sample. We identify significant in-host variation in 27 genes, including antibiotic resistance genes, metabolic genes and genes known to modulate host innate immunity and confirm several to be under positive selection by assessing phylogenetic convergence across a genetically diverse sample of 20,352 isolates.

SUBMITTER: Vargas R

PROVIDER: S-EPMC7884073 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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In-host population dynamics of <i>Mycobacterium tuberculosis</i> complex during active disease.

Vargas Roger R Freschi Luca L Marin Maximillian M Epperson L Elaine LE Smith Melissa M Oussenko Irina I Durbin David D Strong Michael M Salfinger Max M Farhat Maha Reda MR

eLife 20210201

Tuberculosis (TB) is a leading cause of death globally. Understanding the population dynamics of TB's causative agent <i>Mycobacterium tuberculosis</i> complex (Mtbc) in-host is vital for understanding the efficacy of antibiotic treatment. We use longitudinally collected clinical Mtbc isolates that underwent Whole-Genome Sequencing from the sputa of 200 patients to investigate Mtbc diversity during the course of active TB disease after excluding 107 cases suspected of reinfection, mixed infectio ...[more]

PMID: 33522489

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Project description:BackgroundStudying within-host genetic diversity of Mycobacterium tuberculosis (Mtb) in patients during treatment may identify adaptations to antibiotic and immune pressure. Understanding the significance of genetic heteroresistance, and more specifically heterozygous resistance-associated variants (RAVs), is clinically important given increasing use of rapid molecular tests and whole genome sequencing (WGS).MethodsWe analyse data from six studies in KwaZulu-Natal, South Africa. Most patients (>75%) had baseline rifampicin resistance. Sputum was collected for culture at baseline and at between two and nine intervals until month six. Positive cultures underwent WGS. Mixed infections and reinfections were excluded from analysis.FindingsBaseline Mtb overall genetic diversity (at treatment initiation or major change to regimen) was associated with cavitary disease, not taking antiretroviral therapy if HIV infected, infection with lineage 2 strains and absence of second-line drug resistance on univariate analyses. Baseline genetic diversity was not associated with six-month outcome. Genetic diversity increased from baseline to weeks one and two before returning to previous levels. Baseline genetic heteroresistance was most common for bedaquiline (6/10 [60%] of isolates with RAVs) and fluoroquinolones (9/62 [13%]). Most patients with heterozygous RAVs on WGS with sequential isolates available demonstrated RAV persistence or fixation (17/20, 85%). New RAVs emerged in 9/286 (3%) patients during treatment. We could detect low-frequency RAVs preceding emergent resistance in only one case, although validation of deep sequencing to detect rare variants is required.InterpretationIn this study of single-strain Mtb infections, baseline within-host bacterial genetic diversity did not predict outcome but may reveal adaptations to host and drug pressures. Predicting emergent resistance from low-frequency RAVs requires further work to separate transient from consequential mutations.FundingWellcome Trust, NIH/NIAID.

Dataset Information

In-host population dynamics of Mycobacterium tuberculosis complex during active disease.

Publications

In-host population dynamics of <i>Mycobacterium tuberculosis</i> complex during active disease.

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