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Within patient microevolution of Mycobacterium tuberculosis correlates with heterogeneous responses to treatment.

ABSTRACT: Genetic heterogeneity of Mycobacterium tuberculosis (MTB) within a patient has caused great concern as it might complicate antibiotic treatment and cause treatment failure. But the extent of genetic heterogeneity has not been described in detail nor has its association with heterogeneous treatment response. During treatment of a subject with MDR-TB, serial computed tomography (CT) scans showed this subject had six anatomically discrete lesions and they responded to treatment with disparate kinetics, suggesting heterogeneous MTB population may exist. To investigate this heterogeneity, we applied deep whole genome sequencing of serial sputum isolates and discovered that the MTB population within this patient contained three dominant sub-clones differing by 10?~?14 single nucleotide polymorphisms (SNPs). Differential mutation patterns in known resistance alleles indicated these sub-clones had different drug-resistance patterns, which may explain the heterogeneous treatment responses between lesions. Our results showed clear evidence of branched microevolution of MTB in vivo, which led to a diverse bacterial community. These findings indicated that complex sub-populations of MTB might coexist within patient and contribute to lesions' disparate responses to antibiotic treatment.

SUBMITTER: Liu Q

PROVIDER: S-EPMC4664930 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Within patient microevolution of Mycobacterium tuberculosis correlates with heterogeneous responses to treatment.

Liu Qingyun Q Via Laura E LE Luo Tao T Liang Lili L Liu Xin X Wu Sufang S Shen Qingyu Q Wei Wang W Ruan Xianglin X Yuan Xing X Zhang Guolong G Barry Clifton E CE Gao Qian Q

Scientific reports 20151201

Genetic heterogeneity of Mycobacterium tuberculosis (MTB) within a patient has caused great concern as it might complicate antibiotic treatment and cause treatment failure. But the extent of genetic heterogeneity has not been described in detail nor has its association with heterogeneous treatment response. During treatment of a subject with MDR-TB, serial computed tomography (CT) scans showed this subject had six anatomically discrete lesions and they responded to treatment with disparate kinet ...[more]

PMID: 26620446

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Project description:BackgroundWhole-genome sequencing has shown that the Mycobacterium tuberculosis infection process can be more heterogeneous than previously thought. Compartmentalized infections, exogenous reinfections, and microevolution are manifestations of this clonal complexity. The analysis of the mechanisms causing the microevolution -the genetic variability of M. tuberculosis at short time scales- of a parental strain into clonal variants with a patient is a relevant issue that has not been yet completely addressed. To our knowledge, a whole genome sequence microevolution analysis in a single patient with inadequate adherence to treatment has not been previously reported.Case presentationIn this work, we applied whole genome sequencing analysis for a more in-depth analysis of the microevolution of a parental Mycobacterium tuberculosis strain into clonal variants within a patient with poor treatment compliance in Argentina. We analyzed the whole-genome sequence of 8 consecutive Mycobacterium tuberculosis isolates obtained from a patient within 57-months of intermittent therapy. Nineteen mutations (9 short-term, 10 fixed variants) emerged, most of them associated with drug resistance. The first isolate was already resistant to isoniazid, rifampicin, and streptomycin, thereafter the strain developed resistance to fluoroquinolones and pyrazinamide. Surprisingly, isolates remained susceptible to the pro-drug ethionamide after acquiring a frameshift mutation in ethA, a gene required for its activation. We also found a novel variant, (T-54G), in the 5' untranslated region of whiB7 (T-54G), a region allegedly related to kanamycin resistance. Notably, discrepancies between canonical and phage-based susceptibility testing to kanamycin were previously found for the isolate harboring this mutation. In our patient, microevolution was mainly driven by drug selective pressure. Rare short-term mutations fixed together with resistance-conferring mutations during therapy.ConclusionsThis report highlights the relevance of whole-genome sequencing analysis in the clinic for characterization of pre-XDR and MDR resistance profile, particularly in patients with incomplete and/or intermittent treatment.

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.

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Within patient microevolution of Mycobacterium tuberculosis correlates with heterogeneous responses to treatment.

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Within patient microevolution of Mycobacterium tuberculosis correlates with heterogeneous responses to treatment.

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