Drifting to victory: resolving the paradox of M. tuberculosis evolution

项目摘要/摘要 结核病(TB)是世界范围内主要的传染病死亡原因。虽然结核病是可以治疗的， 治疗过程漫长、复杂，许多人难以忍受。结核分枝杆菌 也很容易获得抗药性，全球控制结核病的努力受到日益严重的问题的威胁 抗药性。结核分枝杆菌能够聚集成能够抵抗致命剂量的生物膜群落。 这一现象可能会造成治疗和控制结核病的困难。我们有 开发了一个体外系统来研究结核分枝杆菌在生物膜中的适应情况。利用对这些实验的分析 与具有良好特征的结核分枝杆菌自然种群相比，我们发现结核分枝杆菌菌株 通过少量的遗传差异表现出令人惊讶的表型差异。我们的 初步数据表明，这些变化背后的监管机制。将这些数据与我们 结核分枝杆菌进化种群基因组学在区域和全球范围内的最新发现，我们假设 结核分枝杆菌的适应发生在单个宿主的规模上，而大规模现象主要是一种制约因素 关于改编。我们现在的主要目标是描述观察到的表型背后的机制 这些自然种群和实验种群的差异。

PROJECT SUMMARY/ABSTRACT Tuberculosis (TB) is the leading cause of death due to an infectious disease worldwide. Although TB is treatable, treatments are prolonged, complex, and difficult for many people to tolerate. Mycobacterium tuberculosis (M. tb) also readily acquires drug resistance and global efforts to control TB are threatened by the increasing problem of drug resistance. M. tb is capable of assembling into biofilm communities capable of withstanding lethal doses of antibiotics and this phenomenon likely contributes to difficulties in treating and controlling TB. We have developed an in vitro system to study adaptation M. tb within biofilms. Leveraging analyses of these experimental populations with those of a well characterized natural population of M. tb, we discovered that M. tb strains separated by a small number of genetic differences exhibit a surprising array of phenotypic differences. Our preliminary data point to regulatory mechanisms underlying these changes. Contextualizing these data with our recent discoveries in M.tb evolutionary population genomics at regional and global scales, we hypothesize that M. tb adaptation occurs at the scale of individual hosts while large scale phenomena act primarily as a constraint on adaptation. Our major objective now is to delineate the mechanisms underlying observed phenotypic differences in these natural and experimental populations.