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

使用结核分枝杆菌基因组预测结核病病理、耐药性获得和识别社区传播位点

• 批准号: 10598532
• 负责人: ROBERT H GILMAN
• 金额: $ 65.2万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10598532
• 关键词: Age; Americas; Bacteria; Bacterial Genes; Biological Assay; Biological Markers; Cessation of life; Chest; Clinical; Collection; Communicable Diseases; Communities; Confounding Factors (Epidemiology); Contact Tracing; Data; Data Set; Diagnosis; Disease; Disputes; Drug resistance; Drug resistance in tuberculosis; Ecology; Event; Genetic; Genetic Polymorphism; Genome; Genotype; Home; In Vitro; Incidence; Infectious Agent; Laboratories; Link; M. tuberculosis genome; Maps; Metadata; Monitor; Pathology; Patients; Peru; Pharmaceutical Preparations; Phylogenetic Analysis; Phylogeny; Population; Population Heterogeneity; Predisposition; Questionnaires; Radiology Specialty; Sampling; Site; Techniques; Thoracic Radiography; Time; Treatment Protocols; Tuberculosis; Variant; acquired drug resistance; bacterial genetics; community transmission; drug resistance development; genetic association; genome sequencing; genome wide association study; genomic biomarker; novel; pathogen genome; personalized medicine; prevent; sex; socioeconomics; suburb; transmission process; whole genome

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.

项目摘要 秘鲁在美洲有第二高结核病（TB）疾病[1]。尽管造成了 由于任何单一药物的传染病，全球死亡人数最多，尚未研究 病原体基因组对放射学参与程度对TB病理学的影响 胸部X光片。因此，我们的第一个目的是将种群水平的基因组测序数据与 放射学数据以及链接的临床和人口元数据，以确定使用新型多元基因组 广泛关联（GWAS）技术是结核病病理的细菌基因组生物标志物 在房屋外发生的传播事件后，超过80％的结核病疾病出现[2]。 因此，了解社区中发生在何时，何时何地传输事件是至关重要的 为了干预并防止疾病的传播。识别传输站点，从而 预防传播对于减少原发性耐药性的扩散至关重要[3]。因此，我们的第二个 目的是将整个基因组测序与实时GPS监控和最新的人群水平一起使用 在空间生态映射分析中，相对于匹配的控件，发现了结核病传输的新位点 获得的耐药性也对全球耐药性燃烧产生了重大贡献[4]。结核病如何应变 基因型影响耐药性的获取仍然存在争议和不足的理解[5-11]。 确定哪种遗传背景与获得对特定药物的耐药性最重要 会使患有药物易感性结核病患者接受个性化治疗方案，以最大程度地减少 在该遗传背景上的耐药性发展。因此，我们的第三个目标是使用一套独特的 >在秘鲁在20年内在秘鲁收集的9000种细菌菌株，从而推断出， 遗传背景与耐药性获取有关；然后在实验室中确认这些发现 并在类似的摩尔多瓦数据集收集> 3000株的收藏集中。 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 电阻[12]。我们还确定了大量结核病传播的新社区站点[13] 以及确定与药物中病理学独立相关的推定细菌遗传多态性 抗性结核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 病理学，发现结核病传播的新位点，并鉴定细菌与药物的遗传关联 抵抗采集。