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

项目概要1 本项目的前提是结核分枝杆菌（MTB）耐药性 在常规培养基上通过标准体外DST测量的表型可能不 包括对影响患者结果的药物治疗的全部反应。在 在以前的工作中，我们已经鉴定了赋予药物耐受性的MTB突变， “耐药”临床菌株的条件性耐药性。我们假设 对治疗没有表现出早期和强烈临床反应的患者可能 感染了具有这些表型的突变菌株。如果这被证明是 诚然，通过使用快速诊断工具， 这将允许临床医生修改药物治疗以获得更好的结果。 本研究的目的是确定1）次优的细菌遗传决定因素 患者对结核病治疗的反应。我们将进一步描述来自 对结核病治疗有反应和没有反应的人， 替代非常规培养基，其对替代培养基的平均抑制浓度 媒体和他们的转录签名。我们希望能够识别特定的突变， 与不同生长特征相关的转录标记， 这些将与抗生素耐受性和抗性表型相关。 我们将在不同国家（秘鲁和 蒙古），招募活动性结核病患者，我们将对其进行中期和最终随访 根据临床标准测量的治疗结果。几乎所有以前的研究 临床治疗结果依赖于微生物测定来确定治疗 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。我们在此提出一组临床评估， 测量肺功能、炎症反应和呼吸道症状， 我们希望在有效的结核病治疗的头两个月内有所改善。一旦 我们从对治疗反应不佳的人身上识别和分离结核菌株， 我们将对这些菌株进行测序，并进行全基因组关联研究， 与这些结果相关的特定变量。

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.