Bacterial Determinants of Tuberculosis Susceptibiliy

结核病易感性的细菌决定因素

• 批准号: 10219088
• 负责人: SARAH FORTUNE
• 金额: $ 41.88万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-05 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10219088
• 关键词: Africa; Alleles; Antibiotics; Bacille Calmette-Guerin vaccination; Bacteria; Bar Codes; Biochemical; Biological; Characteristics; Clinical; Collection; Data; Demography; Disease; Evolution; Experimental Models; Face; Fortune; Genes; Genetic; Genetic Determinism; Genetic Markers; Genetic Polymorphism; Genomics; Genotype; Growth; Heterogeneity; Human; Human Genetics; Immune response; Individual; Infection; Integration Host Factors; Libraries; Maps; Meningitis; Modeling; Modernization; Mus; Mycobacterium tuberculosis; Outcome; Pathway interactions; Persons; Phenotype; Population; Population Genetics; Predisposition; Progressive Disease; Specificity; Standardization; System; T-Lymphocyte; TLR2 gene; Testing; Tuberculosis; Variant; Vietnam; Virulence; Virulent; bacterial genetics; base; cohort; epidemiologic data; fitness; genetic approach; genetic association; genetic testing; genome sequencing; human disease; human pathogen; mouse model; mycobacterial; pathogen; preference; social; therapeutic evaluation; trait; transposon sequencing; vaccine efficacy; vaccine evaluation; whole genome

Project 2: Bacterial Determinants of Susceptibility Abstract: The outcome of tuberculosis infection varies tremendously between individuals; most people show no signs of disease but some people will develop progressive disease. These differences in outcome seem to arise both because of differences between people but also because of differences between the strains of Mycobacterium tuberculosis with which they are infected. Indeed, human genetic differences seem to interact with bacterial differences such that the same bacterium may be able to cause disease in one host but not another and similarly, one person may be susceptible to a given bacterium but not another. In this project, we seek to understand this intersection of bacterial features with host genetics, which we term “host-pathogen preference”. In Aim 1, we will define the bacterial factors that influence host-pathogen preference by testing the growth of a very large number of M. tuberculosis strains in a panel of mice bred to be highly diverse (the CC mice). We will identify bacterial and host genetic markers for interactions that are very likely to cause disease and will test the ability of these markers to predict human disease. Aim 2, we will determine the mechanisms by which some bacterial strains are more virulent than others. Finally, in Aim 3, we will test the hypothesis that BCG vaccination protects against infection with some M. tuberculosis strains but not others. These studies will also allow us to develop experimental models of M. tuberculosis infection that reflect the diversity of bacteria that humans face and provide an avenue for more successful vaccine and therapeutic testing.

项目 2：细菌敏感性决定因素 抽象的： 结核感染的结果因人而异，大多数人没有表现出任何迹象。 疾病，但有些人会发展为进行性疾病。这些结果的差异似乎都是两者兼而有之。 因为人与人之间的差异，也因为分枝杆菌菌株之间的差异 事实上，人类基因差异似乎与细菌相互作用。 差异使得同一种细菌可能能够在一个宿主中引起疾病​​，但不能在另一个宿主中引起疾病​​，并且 同样，一个人可能对某种细菌敏感，但对另一种细菌则不然。在这个项目中，我们力求做到这一点。 了解细菌特征与宿主遗传学的交叉点，我们称之为“宿主-病原体” 在目标 1 中，我们将通过测试来定义影响宿主-病原体偏好的细菌因素。 在一组高度多样化的小鼠中生长出大量结核分枝杆菌菌株（ CC 小鼠）我们将识别很可能引起相互作用的细菌和宿主遗传标记。 目标 2，我们将确定这些标记物预测人类疾病的能力。 最后，在目标 3 中，我们将测试某些细菌菌株比其他菌株更具毒性的机制。 假设卡介苗接种可以防止某些结核分枝杆菌菌株的感染，但不能防止其他结核分枝杆菌菌株的感染。 这些研究还将使我们能够开发结核分枝杆菌感染的实验模型，以反映 人类面临的细菌多样性，为更成功的疫苗和治疗提供了途径 测试。