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

项目总结 秘鲁是美洲结核病发病率第二高的国家[1]。尽管造成了 世界上死于任何单一病原体传染病的人数最多，目前还没有研究检查 病原体基因组对结核病病理的影响，根据放射学受累程度对 胸部X光片。因此，我们的第一个目标是将种群水平的基因组测序数据与 放射学数据和相关联的临床和人口学元数据，以确定使用新的多变量基因组 广协技术--结核病病理的细菌基因组生物标记物 超过80%的结核病是在家庭以外的传播事件之后发生的[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。识别传播点，介入，从而 预防传播对于减少原发耐药性的传播至关重要[3]。因此，我们的第二个 目的是使用种群水平的全基因组测序与实时GPS监测和最新的 在空间生态图谱分析中发现与匹配对照相比新的结核病传播地点 获得性耐药性也大大加重了全球的耐药性负担[4]。结核病是如何产生的 基因型影响耐药性的获得仍然存在争议，而且了解还不够充分[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 将使对药物敏感的结核病患者能够接受个性化的治疗方案，将 在这种遗传背景下，抗药性的发展。因此，我们的第三个目标是使用一组独特的 20多年来在秘鲁从种群水平收集的9000株细菌菌株，以进行系统发育推断 遗传背景与耐药性的获得有关；然后在实验室中证实这些发现 以及在摩尔多瓦的一个类似的3000株菌株的数据集上。 初步研究确定了一种与药物高度相关的结核病细菌遗传背景 阻力[12]。我们还确定了发生重大结核病传播的新的社区地点[13] 以及鉴定与药物中的病理独立相关的假定细菌遗传多态 耐药结核病。我们提议的研究可能有助于减少该地区的结核病传播，识别新的生物标志物 病理学，发现新的结核病传播部位，并确定细菌基因与药物的联系 阻力收购。

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.