Using the Mycobacterium tuberculosis Genome to Predict Tuberculosis Pathology, Drug Resistance Acquisition and Identify Community Transmission Sites

项目摘要 秘鲁是美洲结核病发病率第二高的国家[1]。尽管造成了 由于任何单一病原体传染病，全球死亡人数最多，但尚未有研究调查 病原体基因组对结核病病理学的影响，其定义为对结核病的放射性累及程度。 胸片。因此，我们的第一个目标是将联合收割机群体水平的基因组测序数据与 放射学数据和相关的临床和人口统计学元数据，以使用新的多变量基因组来确定 广泛关联（GWAS）技术，结核病病理学的细菌基因组生物标志物 超过80%的结核病是在家庭以外发生的传播事件后发生的[2]。 因此，了解社区中传播事件发生的地点、时间和频率至关重要 以干预和防止疾病的传播。确定传播部位，进行干预， 防止传播对减少原发性耐药性的传播至关重要[3]。因此，我们的第二 目的是利用群体水平的全基因组测序，结合真实的实时GPS监测和最新的 在空间生态学绘图分析中，发现与匹配对照相比的结核病传播新位点 获得性耐药性也是全球耐药性负担的重要组成部分[4]。结核菌株如何 基因型影响耐药性的获得仍然存在争议，而且认识不足[5-11]。 确定哪种遗传背景与获得对特定药物的耐药性最相关 将使药物敏感性结核病患者能够接受个性化的治疗方案， 在遗传背景上产生耐药性。因此，我们的第三个目标是使用一套独特的 在秘鲁收集了超过9000株细菌菌株，在20年的人口水平上， 遗传背景与耐药性获得相关;然后在实验室中确认这些发现 并且在>3000个菌株的类似的摩尔多瓦数据集集合上。 初步研究已经确定了与药物高度相关的结核病细菌遗传背景 阻力[12]。我们还确定了新的结核病严重传播的社区地点[13]， 以及鉴定与药物中的病理学独立相关的推定细菌遗传多态性， 耐药结核病。我们提出的研究可能有助于减少该地区的结核病传播，确定新的生物标志物， 发现结核病传播的新位点，并确定细菌遗传与药物 电阻采集

PROJECT SUMMARY Peru has the second highest incidence of tuberculosis (TB) disease in the Americas [1]. Despite causing the largest number of deaths worldwide due to any single agent infectious disease, no study has yet examined the influence of the pathogen genome on TB pathology as defined by the extent of radiological involvement on the chest radiograph. Therefore, our first Aim is to combine population level genome sequencing data with radiological data and linked clinical and demographic metadata to determine using novel multivariate genome wide association (GWAS) techniques the bacterial genomic biomarkers of TB pathology More than 80% of TB disease arises following a transmission event that occurs outside the home [2]. Understanding where, when and how frequently transmission events occur in the community is therefore critical in order to intervene and prevent spread of the disease. Identifying transmission sites, intervening and thereby preventing transmission is critical to diminishing the spread of primary drug resistance [3]. Therefore, our second Aim is to use population level whole genome sequencing together with real time GPS monitoring and the latest in spatial ecology mapping analysis to uncover new sites of TB transmission relative to matched controls Acquired drug resistance also contributes significantly to the global burden of drug resistance [4]. How TB strain genotype influences the acquisition of drug resistance remains disputed and insufficiently understood [5–11]. Identifying which genetic background is most associated with the acquisition of drug resistance to specific drugs would enable patients with drug susceptible TB to receive a personalized treatment regimen that minimizes the development of drug resistance on that genetic background. Therefore, our third aim is to use a unique set of >9000 bacterial strains collected in Peru at the population level over 20 years to phylogenetically infer which genetic background is associated with drug resistance acquisition; then confirm these findings in the laboratory and on a similar Moldovan dataset collection of >3000 strains. Preliminary studies have identified a TB bacterial genetic background that is highly associated with drug resistance [12]. We have also identified new community sites where significant TB transmission occurs [13] as well as identifying putative bacterial genetic polymorphisms independently associated with pathology in drug resistant TB. Our proposed study could help to diminish TB transmission in the region, identify new biomarkers of pathology, uncover new sites of TB transmission, and identify the bacterial genetic associations with drug resistance acquisition.