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

项目总结/摘要 结核病（TB）是全球范围内因传染病导致死亡的主要原因。虽然结核病是可以治疗的， 治疗是长期的、复杂的，并且许多人难以忍受。结核分枝杆菌（M.结核病） 而且很容易获得耐药性，全球控制结核病的努力受到日益严重的问题的威胁 抗药性的证据。M.结核病能够聚集成能够承受致死剂量的生物膜群落 这种现象可能导致治疗和控制结核病的困难。我们有 发展了一个体外系统来研究适应M.生物膜内的结核病。利用对这些实验的分析 种群与M. tb，我们发现M. tb菌株 由少量遗传差异分开的基因组表现出令人惊讶的一系列表型差异。我们 初步数据表明了这些变化背后的监管机制。将这些数据与我们的 最近在区域和全球范围内结核分枝杆菌进化群体基因组学的发现，我们假设， M.结核病适应发生在个体宿主的规模上，而大规模的现象主要是一种限制。 关于适应。我们现在的主要目标是描述观察到的表型 这些自然和实验群体的差异。

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.