Within patient microevolution of Mycobacterium tuberculosis correlates with heterogeneous responses to treatment.
Within patient microevolution of Mycobacterium tuberculosis correlates with heterogeneous responses to treatment.
复制标题
患者体内结核分枝杆菌的微进化与治疗的异质反应相关。
DOI：
10.1038/srep17507
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发表时间：
2015-12-01
影响因子：
4.6
通讯作者：
Gao Q
中科院分区：
文献类型：
--
作者：
Liu Q;Via LE;Luo T;Liang L;Liu X;Wu S;Shen Q;Wei W;Ruan X;Yuan X;Zhang G;Barry CE 3rd;Gao Q
结核分枝杆菌（MTB）在患者体内的遗传异质性引起了极大的关注，因为它可能使抗生素治疗复杂化并导致治疗失败。但遗传异质性的程度尚未详细描述，也没有其与异质性治疗反应的关联。在治疗MDR-TB受试者期间，连续计算机断层扫描（CT）显示该受试者有6个解剖学上离散的病变，它们对治疗的反应具有不同的动力学，表明可能存在异质性MTB人群。为了研究这种异质性，我们对一系列痰液分离株进行了深度全基因组测序，发现该患者体内的MTB群体包含3个优势亚克隆，差异为10 ~ 14个单核苷酸多态性（SNP）。已知耐药等位基因的差异突变模式表明这些亚克隆具有不同的耐药模式，这可以解释病变之间的异质性治疗反应。我们的研究结果表明，明确的证据分支微进化的MTB在体内，这导致了一个多样化的细菌群落。这些发现表明，复杂的MTB亚群可能在患者体内共存，并导致病变对抗生素治疗的不同反应。
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.