Metabolic adaptions of Mycobacterium tuberculosis at diverse host-pathogen interfaces

结核分枝杆菌在不同宿主-病原体界面的代谢适应

• 批准号: 10630740
• 负责人: DAVID Branch MOODY
• 金额: $ 54.38万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10630740
• 关键词: Animal Model; Antitubercular Agents; Bacterial Genes; CRISPR interference; CRISPR library; Disease; Disease Outcome; Drug Targeting; Encapsulated; Epithelial; Essential Genes; Funding; Genes; Genetic; Genetic Variation; Genome Mappings; Genotype; Grant; Granuloma; Growth; House mice; Human; Inbred Mouse; Inbred Strain; Inbred Strains Mice; Individual; Infection; Integration Host Factors; Lesion; Libraries; Link; Lipids; Measures; Metabolic; Metabolism; Modeling; Mosaicism; Mouse Strains; Mus; Mycobacterium tuberculosis; Nucleotides; Outcome; Parents; Phenotype; Population; Pre-Clinical Model; Process; Quantitative Trait Loci; Recombinants; Reproducibility; Resolution; Resources; Shapes; Site; System; Technology; Tuberculosis; Variant; Virulence; Work; bacterial genetics; base; cohort; disease diagnostic; genome wide association study; genome-wide; genomic locus; human disease; improved; in vivo; mammalian genome; mouse model; mutant; novel; parent grant; pathogen; reference genome; response; stem; trait; transposon sequencing; tuberculosis treatment

Metabolic adaptions of Mycobacterium tuberculosis at diverse host-pathogen interfaces ABSTRACT Defining the mechanisms through which Mycobacterium tuberculosis (Mtb) metabolites impact human tuberculosis (TB) disease, diagnostics and treatment will require the implementation of model animal systems that are both tractable and faithfully replicate the TB disease states observed in humans. To overcome the limited genetic and phenotypic diversity shown in standard C57BL/6J, here we propose to leverage the comprehensive panel of Collaborative Cross (CC) mice, a genetically diverse panel of recombinant inbred mice. We have previously shown that the CC encompasses a broad spectrum of TB disease traits and infection microenvironments, exceeding the phenotypic spectrum observed in classical inbred strains. Based on previous TnSeq studies and as part of the parent TBRU grant (“Metabolic determinants of Mtb virulence, vulnerability and variation”; 1U19AI162584-02), we have ranked Mtb metabolic genes that were linked to Mtb virulence or control lipid variation in Mtb strains that infect humans. Of 19 high value Mtb metabolic genes identified, only one controlled growth in the conventional C57BL/6J (BL6) mouse strain. However, more than half the mutants studied showed in vivo growth phenotypes when screened across CC mouse strains. Further, through study of several of the CC host genetic backgrounds in which individual bacterial genes do or do not control in vivo Mtb survival, we are able to start to define the host factors in control of Mtb response. The current application will now extend these studies to focus on a targeted bacterial lipid library of CRISPRi mutants in conjunction with the comprehensive panel of CC mice. By infecting 60 distinct CC genotypes with the targeted lipid CRISPRi library, the metabolic vulnerabilities of Mtb will be comprehensively defined in genetically diverse hosts. By using bacterial mutant abundance as a phenotypic trait, we will conduct quantitative trait loci (QTL) mapping across the CC panel to identify the host loci underlying the lipid requirements of Mtb infection. Altogether these dual host and pathogen approaches will identify the host-Mtb lipid interactions that can be targeted for tuberculosis treatment.

结核分枝杆菌在不同宿主-病原体界面的代谢适应 抽象的 定义结核分枝杆菌 (Mtb) 代谢物影响人类的机制 结核病、诊断和治疗需要实施模型动物系统 既易于处理又忠实地复制了在人类中观察到的结核病状态。 标准 C57BL/6J 中显示的遗传和表型多样性有限，在这里我们建议利用 协作杂交 (CC) 小鼠的综合小组，重组近交系的遗传多样性小组 我们之前已经证明 CC 包含广泛的结核病特征和 感染微环境，超过了在经典近交系中观察到的表型谱。 之前的 TnSeq 研究以及作为母公司 TBRU 资助的一部分（“Mtb 毒力的代谢决定因素， 1U19AI162584-02），我们对与 Mtb 相关的 Mtb 代谢基因进行了排名 感染人类的​​ 19 个高值 Mtb 代谢基因的毒力或控制脂质变异。 然而，在传统的 C57BL/6J (BL6) 小鼠品系中，只有一种能够控制生长。 在对 CC 小鼠品系进行筛选时，一半的研究突变体显示出体内生长表型。 通过研究几种 CC 宿主遗传背景，其中单个细菌基因起作用或不起作用 为了控制体内 Mtb 的存活，我们能够开始定义控制 Mtb 反应的宿主因素。 目前的申请现在将扩展这些研究，重点关注 CRISPRi 的靶向细菌脂质库 通过感染 60 种不同的 CC 基因型，将突变体与 CC 小鼠综合组结合起来。 靶向脂质 CRISPRi 文库，Mtb 的代谢脆弱性将在 通过使用细菌突变体丰度作为表型特征，我们将进行 CC 面板上的数量性状基因座 (QTL) 作图，以确定脂质背后的宿主基因座 Mtb 感染的要求，这些双重宿主和病原体方法将识别宿主 Mtb。 脂质相互作用可作为结核病治疗的目标。

项目成果

Beyond antibiotic resistance: the whiB7 transcription factor coordinates an adaptive response to alanine starvation in mycobacteria.

超越抗生素耐药性：whiB7 转录因子协调分枝杆菌对丙氨酸饥饿的适应性反应。

• 发表时间: 2023-06-05
• 作者: Poulton, Nicholas C;DeJesus, Michael A;Munsamy;Roberts, Cameron G;Azadian, Zachary A;Bosch, Barbara;Lin, Karl Matthew;Li, Shuqi;Rock, Jeremy M
• 通讯作者: Rock, Jeremy M

Unraveling the mechanisms of intrinsic drug resistance in Mycobacterium tuberculosis.

揭示结核分枝杆菌内在耐药机制。

• 发表时间: 2022
• 作者: Poulton, Nicholas C;Rock, Jeremy M
• 通讯作者: Rock, Jeremy M

Mutations in rv0678 Confer Low-Level Resistance to Benzothiazinone DprE1 Inhibitors in Mycobacterium tuberculosis.

rv0678 的突变赋予结核分枝杆菌对苯并噻嗪酮 DprE1 抑制剂的低水平耐药性。

• 发表时间: 2022-09-20
• 影响因子: 4.9
• 作者: Poulton, Nicholas C;Azadian, Zachary A;DeJesus, Michael A;Rock, Jeremy M
• 通讯作者: Rock, Jeremy M

Beyond antibiotic resistance: The whiB7 transcription factor coordinates an adaptive response to alanine starvation in mycobacteria.

超越抗生素耐药性：whiB7 转录因子协调分枝杆菌对丙氨酸饥饿的适应性反应。

• DOI: 10.1016/j.chembiol.2023.12.020
• 发表时间: 2024-01-01
• 期刊: Cell chemical biology
• 影响因子: 8.6
• 作者: Nicholas C. Poulton;M. DeJesus;Vanisha Munsamy;Mariko Kanai;Cameron G Roberts;Zachary A. Azadian;Barbara Bosch;Karl Matthew Lin;Shuqi Li;Jeremy M. Rock
• 通讯作者: Jeremy M. Rock

Aerosolization of Mycobacterium tuberculosis by Tidal Breathing.

通过潮式呼吸雾化结核分枝杆菌。

• 发表时间: 2022-07-15
• 影响因子: 24.7
• 作者: Dinkele, Ryan;Gessner, Sophia;McKerry, Andrea;Leonard, Bryan;Leukes, Juane;Seldon, Ronnett;Warner, Digby F;Wood, Robin
• 通讯作者: Wood, Robin