Diversity of Mycobacterium tuberculosis across Evolutionary Scales.
Diversity of Mycobacterium tuberculosis across Evolutionary Scales.
复制标题
DOI：
10.1371/journal.ppat.1005257
复制
发表时间：
2015
期刊：
影响因子：
6.7
通讯作者：
Pepperell CS
中科院分区：
文献类型：
--
作者：
O'Neill MB;Mortimer TD;Pepperell CS
结核病（TB）是一种全球性突发公共卫生事件。结核分枝杆菌 (M.tb) 的耐药菌株不断出现和传播，凸显了这种病原体的适应性。大多数结核分枝杆菌进化研究都依赖于“宿主间”样本，其中每个结核病患者都由一个结核分枝杆菌分离株代表。然而，结核病患者体内通常携带数十亿结核菌。在这里，我们对宿主内部和宿主之间的结核分枝杆菌基因组数据进行分析，以深入了解影响该病原体遗传多样性的影响。我们发现，结核病患者所拥有的结核分枝杆菌遗传多样性的数量可能存在巨大差异，很可能是疾病严重程度的函数。令人惊讶的是，我们没有发现结核病治疗对结核分枝杆菌多样性有明显影响。在检查结核病宿主内部和之间的结核分枝杆菌样本的基因组数据时，我们发现参与免疫调节细胞包膜脂质的调节、合成和运输的基因反复出现在各种多样性统计测量的极端情况中。在使用不同方法和数据集的其他研究中，许多这些基因已被确定为可能的选择目标。总而言之，这些观察结果表明结核分枝杆菌细胞包膜脂质是宿主内选择的目标。许多这些脂质是致病性分枝杆菌所特有的，在某些情况下，是人类致病性分枝杆菌所特有的。我们推测细胞包膜脂质的快速适应是通过功能冗余、代谢灵活性以及它们介导与宿主相互作用的作用来促进的。结核病（TB）对全球公共卫生构成严重威胁，是传染病导致死亡的第二大原因。病原体结核分枝杆菌 (M.tb) 的耐药性日益增强，阻碍了我们控制结核病的努力。我们需要更好地了解结核病适应情况，以指导制定更有效的结核病治疗和控制策略。本研究的目的是深入了解结核病患者体内结核分枝杆菌的演变。我们发现结核病患者体内存在多种结核分枝杆菌。我们进一步发现的证据表明，细菌种群的进化是为了响应宿主内部环境施加的选择压力。参与细菌细胞包膜脂质和糖脂调节、合成和运输的 M.tb 基因的变化尤其显着。这些发现对药物和疫苗的开发具有重要意义，并提供了对结核病宿主病原体相互作用的深入了解。
Tuberculosis (TB) is a global public health emergency. Increasingly drug resistant strains of Mycobacterium tuberculosis (M.tb) continue to emerge and spread, highlighting adaptability of this pathogen. Most studies of M.tb evolution have relied on ‘between-host’ samples, in which each person with TB is represented by a single M.tb isolate. However, individuals with TB commonly harbor populations of M.tb numbering in the billions. Here, we use analyses of M.tb genomic data from within and between hosts to gain insight into influences shaping genetic diversity of this pathogen. We find that the amount of M.tb genetic diversity harbored by individuals with TB can vary dramatically, likely as a function of disease severity. Surprisingly, we did not find an appreciable impact of TB treatment on M.tb diversity. In examining genomic data from M.tb samples within and between hosts with TB, we find that genes involved in the regulation, synthesis, and transportation of immunomodulatory cell envelope lipids appear repeatedly in the extremes of various statistical measures of diversity. Many of these genes have been identified as possible targets of selection in other studies employing different methods and data sets. Taken together, these observations suggest that M.tb cell envelope lipids are targets of selection within hosts. Many of these lipids are specific to pathogenic mycobacteria and, in some cases, human-pathogenic mycobacteria. We speculate that rapid adaptation of cell envelope lipids is facilitated by functional redundancy, flexibility in their metabolism, and their roles mediating interactions with the host. Tuberculosis (TB) is a grave threat to global public health and is the second leading cause of death due to infectious disease. The causative agent, Mycobacterium tuberculosis (M.tb), has emerged in increasingly drug resistant forms that hamper our efforts to control TB. We need a better understanding of M.tb adaptation to guide development of more effective TB treatment and control strategies. The goal of this study was to gain insight into M.tb evolution within individual patients with TB. We found that TB patients harbor a diverse population of M.tb. We further found evidence to suggest that the bacterial population evolves measurably in response to selection pressures imposed by the environment within hosts. Changes were particularly notable in M.tb genes involved in the regulation, synthesis, and transportation of lipids and glycolipids of the bacterial cell envelope. These findings have important implications for drug and vaccine development, and provide insight into TB host pathogen interactions.