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Dynamics of antibiotic resistant Mycobacterium tuberculosis during long-term infection and antibiotic treatment.

ABSTRACT: For an infecting bacterium the human body provides several potential ecological niches with both internally (e.g. host immunity) and externally (e.g. antibiotic use) imposed growth restrictions that are expected to drive adaptive evolution in the bacterium, including the development of antibiotic resistance. To determine the extent and pattern of heterogeneity generated in a bacterial population during long-term antibiotic treatment, we examined in a monoclonal Mycobacterium tuberculosis infection antibiotic resistant mutants isolated from one patient during a 9-years period. There was a progressive accumulation of resistance mutations in the infecting clone. Furthermore, apparent clonal sweeps as well as co-existence of different resistant mutants were observed during this time, demonstrating that during treatment there is a high degree of dynamics in the bacterial population. These findings have important implications for diagnostics and treatment of drug resistant tuberculosis infections.

SUBMITTER: Mariam SH

PROVIDER: S-EPMC3116863 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Dynamics of antibiotic resistant Mycobacterium tuberculosis during long-term infection and antibiotic treatment.

Mariam Solomon H SH Werngren Jim J Aronsson Joakim J Hoffner Sven S Andersson Dan I DI

PloS one 20110616 6

For an infecting bacterium the human body provides several potential ecological niches with both internally (e.g. host immunity) and externally (e.g. antibiotic use) imposed growth restrictions that are expected to drive adaptive evolution in the bacterium, including the development of antibiotic resistance. To determine the extent and pattern of heterogeneity generated in a bacterial population during long-term antibiotic treatment, we examined in a monoclonal Mycobacterium tuberculosis infecti ...[more]

PMID: 21698208

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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.

Project description:The immune control of tuberculosis (TB) infection could be influenced by pregnancy. To elucidate this, we longitudinally characterized Mycobacterium tuberculosis (Mtb)-specific and nonspecific immune responses in women during pregnancy and postpartum. HIV-uninfected women without past or current active TB, and with blood samples available from the 1st/2nd trimester, 3rd trimester, and 9 months postpartum, were identified at Ethiopian antenatal care clinics. Twenty-two TB+ women and 10 TB- women, defined according to Mtb-stimulated interferon-γ levels (≥0.35 and <0.20 IU/mL, respectively, in the Quantiferon-TB Gold-Plus assay), were included in the study. Longitudinal dynamics of six cytokines (IL-1ra, IL-2, IP-10, MCP-2, MCP-3, and TGF-β1) were analyzed in supernatants from Mtb-stimulated and unstimulated whole blood. In TB+ women, Mtb-specific expression of IL-2 and IP-10 was higher at 3rd compared to 1st/2nd trimester (median 139 pg/mL versus 62 pg/mL, P = 0.006; 4,999 pg/mL versus 2,310 pg/mL, P = 0.031, respectively), whereas level of Mtb-triggered TGF-β1 was lower at 3rd compared to 1st/2nd trimester (-6.8 ng/mL versus 2.3 ng/mL, P = 0.020). Unstimulated IL-2, IP-10, and MCP-2 levels were increased postpartum, compared with those noted during pregnancy, in TB+ women. Additionally, postpartum levels of proinflammatory cytokines in unstimulated blood were higher in TB+ women, than in TB- women. None of the women developed active TB during follow-up. Taken together, dynamic changes of Mtb-specific cytokine expression revealed during the 3rd trimester in TB+ women indicate increased Mtb-antigen stimulation at later stages of pregnancy. This could reflect elevated bacterial activity, albeit without transition to active TB, during pregnancy. IMPORTANCE Tuberculosis (TB) is globally one of the most common causes of death, and a quarter of the world's population is estimated to have TB infection. The risk of active TB is increased in connection to pregnancy, a phenomenon that could be due to physiological immune changes. Here, we studied the effect of pregnancy on immune responses triggered in HIV-uninfected women with TB infection, by analyzing blood samples obtained longitudinally during pregnancy and after childbirth. We found that the dynamics of Mtb-specific and nonspecific immune responses changed during pregnancy, especially in later stages of pregnancy, although none of the women followed in this study developed active TB. This suggests that incipient TB, with elevated bacterial activity, occurs during pregnancy, but progression of infection appears to be counteracted by Mtb-specific immune responses. Thus, this study sheds light on immune control of TB during pregnancy, which could be of importance for future intervention strategies.

Dataset Information

Dynamics of antibiotic resistant Mycobacterium tuberculosis during long-term infection and antibiotic treatment.

Publications

Dynamics of antibiotic resistant Mycobacterium tuberculosis during long-term infection and antibiotic treatment.

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