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

Liu Q, Via LE, Luo T, Liang L, Liu X, Wu S, Shen Q, Wei W, Ruan X, Yuan X, Zhang G, Barry CE, Gao Q - Sci Rep (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Institutes of Biomedical Sciences and Institute of Medical Microbiology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.

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.

No MeSH data available.


Related in: MedlinePlus

CT images from the subject at weeks 0 and 8.These images show six discrete lesion sites co-occurring in this subject. Each lesion is shown as a separate color and the extent represents “hard” lesion density (from −100 to + 200 Hounsfeld units) (PMID: 25473034). The left images show the results at study entry, prior to receiving TB chemotherapy and the result to the right show the same lesions after eight weeks of treatment. The airways are shown in green and the outline of the individual lungs is shown in transparent grey in the top images (A). In (B) the lesions contained within the left lung only are shown and the image is rotated to view this from the left side, likewise in (C) only lesions in the right lung are shown and the image is viewed from the right. In (D) the right lower lobe lesion, which increases 60% between the two scans is shown with an axial CT slice cut to show that the extent of disease does indeed increase. Rendering and quantification was performed with Amira 5.6.0 (FEI Visualization Sciences Group).
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f1: CT images from the subject at weeks 0 and 8.These images show six discrete lesion sites co-occurring in this subject. Each lesion is shown as a separate color and the extent represents “hard” lesion density (from −100 to + 200 Hounsfeld units) (PMID: 25473034). The left images show the results at study entry, prior to receiving TB chemotherapy and the result to the right show the same lesions after eight weeks of treatment. The airways are shown in green and the outline of the individual lungs is shown in transparent grey in the top images (A). In (B) the lesions contained within the left lung only are shown and the image is rotated to view this from the left side, likewise in (C) only lesions in the right lung are shown and the image is viewed from the right. In (D) the right lower lobe lesion, which increases 60% between the two scans is shown with an axial CT slice cut to show that the extent of disease does indeed increase. Rendering and quantification was performed with Amira 5.6.0 (FEI Visualization Sciences Group).

Mentions: The subject described in this study had a previous history of tuberculosis and was thought to have been successfully treated as a child about 8 years ago. Upon presenting to the hospital with new signs and symptoms of tuberculosis, computed tomography (CT) images revealed bilateral disease with at least six spatially isolated lesions before treatment recommenced (Fig. 1—left panels). These six lesions included at least three moderate to large air pockets suggesting cavitary disease, all of which occurred at the distal end of a quaternary bronchus serving a distinct bronchopulmonary segment. Each of these was therefore potentially in direct contact with the airways and could be contributing bacilli to the sputum. In the left superior lobe there were two discrete apical lesions (red and blue in Fig. 1B), one of which did not appear cavitary. The posterior lesion (red), however, had a modest cavity containing 1.0 ml of air (white solid color in all lesions). The left inferior lobe was highly affected with a large lesion containing a central cavitation that contained 3.5 ml of air (lesion gold, air white in Fig. 1A,B). The right upper and middle lobes had non-cavitary lesions (tan and purple, respectively) but the right lower lobe had a large affected area with two separate air pockets occurring in discrete segments (light blue with two air pockets shown in white).


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

Liu Q, Via LE, Luo T, Liang L, Liu X, Wu S, Shen Q, Wei W, Ruan X, Yuan X, Zhang G, Barry CE, Gao Q - Sci Rep (2015)

CT images from the subject at weeks 0 and 8.These images show six discrete lesion sites co-occurring in this subject. Each lesion is shown as a separate color and the extent represents “hard” lesion density (from −100 to + 200 Hounsfeld units) (PMID: 25473034). The left images show the results at study entry, prior to receiving TB chemotherapy and the result to the right show the same lesions after eight weeks of treatment. The airways are shown in green and the outline of the individual lungs is shown in transparent grey in the top images (A). In (B) the lesions contained within the left lung only are shown and the image is rotated to view this from the left side, likewise in (C) only lesions in the right lung are shown and the image is viewed from the right. In (D) the right lower lobe lesion, which increases 60% between the two scans is shown with an axial CT slice cut to show that the extent of disease does indeed increase. Rendering and quantification was performed with Amira 5.6.0 (FEI Visualization Sciences Group).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4664930&req=5

f1: CT images from the subject at weeks 0 and 8.These images show six discrete lesion sites co-occurring in this subject. Each lesion is shown as a separate color and the extent represents “hard” lesion density (from −100 to + 200 Hounsfeld units) (PMID: 25473034). The left images show the results at study entry, prior to receiving TB chemotherapy and the result to the right show the same lesions after eight weeks of treatment. The airways are shown in green and the outline of the individual lungs is shown in transparent grey in the top images (A). In (B) the lesions contained within the left lung only are shown and the image is rotated to view this from the left side, likewise in (C) only lesions in the right lung are shown and the image is viewed from the right. In (D) the right lower lobe lesion, which increases 60% between the two scans is shown with an axial CT slice cut to show that the extent of disease does indeed increase. Rendering and quantification was performed with Amira 5.6.0 (FEI Visualization Sciences Group).
Mentions: The subject described in this study had a previous history of tuberculosis and was thought to have been successfully treated as a child about 8 years ago. Upon presenting to the hospital with new signs and symptoms of tuberculosis, computed tomography (CT) images revealed bilateral disease with at least six spatially isolated lesions before treatment recommenced (Fig. 1—left panels). These six lesions included at least three moderate to large air pockets suggesting cavitary disease, all of which occurred at the distal end of a quaternary bronchus serving a distinct bronchopulmonary segment. Each of these was therefore potentially in direct contact with the airways and could be contributing bacilli to the sputum. In the left superior lobe there were two discrete apical lesions (red and blue in Fig. 1B), one of which did not appear cavitary. The posterior lesion (red), however, had a modest cavity containing 1.0 ml of air (white solid color in all lesions). The left inferior lobe was highly affected with a large lesion containing a central cavitation that contained 3.5 ml of air (lesion gold, air white in Fig. 1A,B). The right upper and middle lobes had non-cavitary lesions (tan and purple, respectively) but the right lower lobe had a large affected area with two separate air pockets occurring in discrete segments (light blue with two air pockets shown in white).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Institutes of Biomedical Sciences and Institute of Medical Microbiology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.

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.

No MeSH data available.


Related in: MedlinePlus