Human adaptation and transmissibility of Mycobacterium tuberculosis genetic lineages. A genomic epidemiology study to guide TB control

结核分枝杆菌遗传谱系的人类适应和传播性。

• 批准号: 10382446
• 负责人: Maha Farhat
• 金额: $ 25.1万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-05 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10382446
• 关键词: American; Bacteria; Biological; Biological Response Modifiers; Biology; Cause of Death; Cessation of life; Characteristics; Chemoprophylaxis; Clinical; Communicable Diseases; Contact Tracing; Containment; Country; Coupled; DNA; Data; Disease; Disease Progression; Drug resistance; East Asian; Epidemiology; Exposure to; Genes; Genetic; Genetic study; Genotype; Geography; Goals; Human; Immune response; Infection; Infectious Agent; Intercistronic Region; International; Link; Maps; Measures; Modeling; Movement; Mutation; Mycobacterium tuberculosis; Patients; Pattern; Phenotype; Population Surveillance; Positioning Attribute; Proteins; Public Health; Regulator Genes; Research Personnel; Resolution; Risk; Role; Societies; Statistical Models; System; Time; Tuberculosis; Virulence; Work; base; case control; cytokine; design; disease phenotype; disease transmission; disorder control; epidemiologic data; epidemiology study; genetic variant; genome sequencing; genome wide association study; genomic epidemiology; genomic locus; high risk; human pathogen; improved; in vitro Assay; in vitro Model; indexing; innovation; latent infection; novel; pathogen; pathogen genome; stem; surveillance data; tool; transmission process; vaccine development; whole genome

The main causative agent of tuberculosis (TB), Mycobacterium tuberculosis (Mtb), is responsible for more deaths annually than any other single infectious agent. Mtb bacteria are separated into eight genetic lineages and preliminary data supports differences in virulence and transmissibility among them. Globally, Mtb lineages show distinct geographical patterns that parallel that of human subpopulations suggesting co-adaption between host and pathogen. It is unknown if this geographic pattern will continue to be observed in cosmopolitan societies where different human subpopulations live in close proximity, and Mtb lineages have the opportunity to infect ‘naive’ hosts without co-adaptation. Assessing if and why Mtb lineages have variable transmissibility and if they are indeed adapted to different human subpopulations can help guide disease control and improve our understanding of biological host pathogen relationships. Using epidemiological and whole genome sequencing data from an international consortium, this project aims to investigate the relationship between Mtb lineage and disease transmissibility across and within human subpopulations. A genome wide association approach will be employed to fine map specific Mtb genetic loci associated with the transmissibility phenotype. Investigating adaptation between Mtb and its human host will define combinations of Mtb lineage and host ancestry most prone to progression and transmission. This can ultimately help refine disease containment strategies such as latent TB chemoprophylaxis and targeted contact tracing to achieve WHO End TB goals of eliminating TB by 2035.

结核病(TB)的主要病原体结核分枝杆菌(Mtb)每年造成的死亡人数比任何其他单一感染源都要多。结核分枝杆菌被分成八个遗传谱系，初步数据支持它们之间毒力和传播力的差异。在全球范围内，结核分枝杆菌谱系显示出明显的地理模式，与人类亚群的模式相似，表明宿主和病原体之间存在共同适应。目前尚不清楚这种地理模式是否会继续在不同人类亚群生活在一起的大都市社会中观察到，而且结核分枝杆菌血统有机会在没有共同适应的情况下感染“幼稚”的宿主。评估结核分枝杆菌谱系是否以及为什么具有可变的传播性，以及它们是否确实适应不同的人类亚群，有助于指导疾病控制，并提高我们对生物宿主病原体关系的理解。利用一个国际联盟的流行病学和全基因组测序数据，该项目旨在调查结核分枝杆菌血统与疾病在人类亚群之间和内部的传播性之间的关系。全基因组关联方法将被用来精细定位与传播性表型相关的特定Mtb遗传位点。研究结核分枝杆菌与其人类宿主之间的适应性将确定最容易进展和传播的结核分枝杆菌血统和宿主祖先的组合。这最终有助于完善疾病控制战略，如潜伏结核病化学预防和有针对性的接触者追踪，以实现世卫组织到2035年消灭结核病的目标。