High-Throughput Identification of Mycobacterium tuberculosis Persistence Mechanis

结核分枝杆菌持续机制的高通量鉴定

• 批准号: 8566012
• 负责人: Anna DeGraff Tischler
• 金额: $ 222.72万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-24 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8566012
• 关键词: Accounting; Animals; Antibiotics; Bar Codes; Cells; Cost Effectiveness Analysis; Drug Targeting; Genetic Screening; Genome; Growth; Human; Immune; In Vitro; Individual; Infection; Methods; Modeling; Molecular; Mus; Mycobacterium tuberculosis; Population; Tuberculosis; fitness; genome-wide; in vivo Model; mutant; new technology; novel; novel strategies; pulmonary agents; therapeutic target

DESCRIPTION (provided by applicant): Mycobacterium tuberculosis (Mtb), the causative agent of the pulmonary infection tuberculosis, has evaded eradication from the human population due to its extraordinary ability to both persist in latently infected individuals and to generate antibiotic-tolerant persister cells. We hypothesize that different molecular mechanisms account for these two types of Mtb persistence and propose novel high-throughput genetic screens to identify and characterize these mechanisms. We will use a new technology, Tn-seq, that simultaneously identifies and quantifies transposon (Tn) insertion mutants within large random Tn mutant pools by massively parallel sequencing of Tn-genome junctions. Tn-seq has previously been used to analyze fitness of bacterial Tn mutants in various culture conditions in vitro and in some animal infection models in vivo. But Tn-seq has limited utility for studying growth conditions or infection models in which there are narrow colonization bottlenecks. We propose to adapt the Tn-seq method using bar-code sequence tags and multi-plexing to enable cost-effective analysis of smaller Tn mutant pools. We will use Tn-seq combined with infection of genetically modified mice to define on a genome- wide scale the factors that Mtb requires for persistence in the face of specific host adaptive immune defenses. We will additionally use an in vitro antibiotic selection strategy combined with Tn-seq to define factors that Mtb requires for optimal formation of antibiotic-tolerant persister cells. Ultimately, we will expand these results o relevant animal infection models, to demonstrate that the Mtb persistence factors we identify are viable drug targets. Therapeutics targeting these persistence factors would represent novel approaches to tuberculosis control that would sensitize Mtb either to natural host immune defenses or to existing antibiotics.

描述（由申请人提供）：结核分枝杆菌（Mtb）是肺部感染结核病的病原体，由于其在潜伏感染个体中持续存在的非凡能力，并使其无法从人群中根除

项目成果

Phosphate responsive regulation provides insights for ESX-5 function in Mycobacterium tuberculosis.

• DOI: 10.1007/s00294-016-0604-4
• 发表时间: 2016-11
• 期刊: CURRENT GENETICS
• 影响因子: 2.5
• 作者: Elliott, Sarah R.;Tischler, Anna D.
• 通讯作者: Tischler, Anna D.

Phosphate starvation: a novel signal that triggers ESX-5 secretion in Mycobacterium tuberculosis.

• DOI: 10.1111/mmi.13332
• 发表时间: 2016-05
• 期刊: Molecular microbiology
• 影响因子: 3.6
• 作者: Elliott SR;Tischler AD
• 通讯作者: Tischler AD

Mycobacterium tuberculosis Pst/SenX3-RegX3 Regulates Membrane Vesicle Production Independently of ESX-5 Activity.

• DOI: 10.1128/mbio.00778-18
• 发表时间: 2018-06-12
• 期刊: mBio
• 影响因子: 6.4
• 作者: White DW;Elliott SR;Odean E;Bemis LT;Tischler AD
• 通讯作者: Tischler AD