Gerome Wide Association Study of Bacterial Determinants of Clinical Response in Tuberculosis

项目摘要1 该项目的前提是结核分枝杆菌(MTB)的耐药性 用常规培养上的标准体外DSTs测定的表型可能不会 包括对影响患者预后的药物治疗的全方位反应。在……里面 之前的工作，我们已经确定了结核分枝杆菌突变导致药物耐受性和 “耐药”临床菌株的条件性耐药。我们假设 对治疗没有早期和有力的临床反应的患者可能是 感染了具有这些表型突变的菌株。如果这被证明是 是的，通过使用快速诊断工具及早检测到这些突变 这将允许临床医生修改药物治疗以获得更好的结果。 这项研究的目标是确定1)次优的细菌遗传决定因素 患者对结核病治疗的反应。我们将进一步鉴定来自 对结核病治疗的反应和不反应在他们的成长能力方面 交替的非常规介质，它们对交替的平均抑制浓度 媒体和他们的转录签名。我们希望确定特定的突变和 与不同生长特征相关的转录签名，以及 这些与抗生素耐受性和耐药表型有关。 我们将在不同国家的两个现场进行这项纵向研究(秘鲁和 蒙古)，招募活动性结核病患者，我们将对他们进行中期和最终跟踪 以临床标准衡量的治疗结果。几乎所有以前的研究 临床治疗结果依赖于微生物检测来确定治疗效果。 反应，因此没有建立良好的标准来评估治疗反应 包括微生物结果。我们在此建议设计一个临床评估小组 为了测量肺功能、炎症反应和呼吸道症状，所有 我们预计，在有效的结核病治疗的头两个月，这种情况会有所改善。一次 我们从对治疗反应不佳的人身上鉴定和分离出结核病菌株， 我们将对这些菌株进行测序，并进行全基因组关联研究，以确定 与这些结果相关的特定变种。

Summary Project 1 The premise of this project is that Mycobacteria tuberculosis (MTB) drug resistance phenotypes as measured by standard in vitro DSTs on conventional media may not encompass the full range of responses to drug therapy that affect patient outcomes. In previous work, we have identified MTB mutations that confer drug tolerance and conditional drug tolerance among “drug resistant” clinical strains. We hypothesize that patients who do not manifest early and vigorous clinical responses to treatment may be infected with strains with mutations that confer these phenotypes. If this is shown to be true, the early detection of these mutations through the use of rapid diagnostic tools which would allow clinicians to modify drug treatment to achieve better outcomes. The goals of this study are to identify bacterial genetic determinants of 1) sub-optimal patient response to TB treatment. We will further characterize strains from people who respond and do not respond to TB treatment in terms of their ability to be grown on alternate non-conventional media, their mean inhibitory concentrations on alternate media, and their transcriptional signatures. We expect to identify specific mutations and transcriptional signatures that are associated with different growth characteristics and that these will be related to antibiotic tolerance and resistance phenotypes. We will conduct this longitudinal study at two field sites in different countries (Peru and Mongolia), enrolling active TB patients whom we will follow for interim and final treatment outcomes as measured by clinical criteria. Almost all previous studies of clinical treatment outcomes have relied on microbiological assays to determine treatment response so there are no well established norms to assess treatment response that do not include microbiological results. We propose here a panel of clinical assessments designed to measure pulmonary function, inflammatory response and respiratory symptoms, all of which we expect to improve over the first two months of effective TB treatment. Once we identify and isolate TB strains from people with sub-optimal responses to treatment, we will sequence these strains and perform a genome wide association study to identify specific variants associated with these outcomes.