Study of M. tuberculosis under human host selection to identify virulence and barrier lipids (Project 1)

研究人类宿主选择下的结核分枝杆菌以确定毒力和屏障脂质（项目 1）

• 批准号: 10612035
• 负责人: DAVID Branch MOODY
• 金额: $ 25.84万
• 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/10612035
• 关键词: Antimycobacterial Agents; Bacterial Genes; Biochemical; Biological; Biological Process; CRISPR interference; Cell Wall; Chemicals; Citric Acid Cycle; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Color; Communities; Data; Data Set; Databases; Diagnostic; Drug Controls; Drug resistance; Epidemic; Gene Silencing; Genes; Genetic; Genetic Variation; Genetic study; Genomics; Genus Mycobacterium; Goals; High Pressure Liquid Chromatography; Human; Immune; Immune response; Individual; Infection; Knowledge; Laboratories; Link; Lipids; Maps; Mass Spectrum Analysis; Membrane; Membrane Lipids; Metabolic; Metabolism; Mus; Mycobacterium tuberculosis; Names; Nature; Organism; Outcome; Pathway interactions; Patients; Pattern; Penetration; Pharmaceutical Preparations; Phenotype; Population; Research Personnel; Robin bird; Role; South Africa; Structure; Testing; Tuberculosis; Tuberculosis diagnosis; Validation; Variant; Virulence; Virulent; Whole Organism; Wood material; cell envelope; comparative; comparative genomics; experimental study; gene discovery; gene function; gene synthesis; genome sequencing; genome wide association study; genome-wide; in vivo; individual patient; insight; lipid biosynthesis; lipidome; lipidomics; metabolomics; mycobacterial; mycolate; novel diagnostics; novel strategies; novel therapeutics; overexpression; pressure; programs; selective expression; transmission process; tuberculosis treatment; whole genome

Project 1. Study of M. tuberculosis under human host selection to identify virulence and barrier lipids Project Leader: D. Branch Moody Coinvestigators: Kyu Rhee, Jacob Mayfield Collaborating Investigators: Adriaan Minnaard (Core C), Jeremy Rock (Core D), Clare Smith (Core E) ABSTRACT Comparative genomics has served as a dominant paradigm for tracking the tuberculosis (TB) epidemic, understanding Mycobacterium tuberculosis (Mtb) virulence and developing new drugs and diagnostics. Mycobacterial metabolism, in contrast, has been viewed as invariant feature of all clinical Mtb strains. Through comparative metabolomic profiling of ~10,000 lipids among 84 patient-derived Mtb strains, we discovered that Mtb’s pathognomonic lipid envelope shows identifiable patterns of variance among strains circulating among human populations. To determine the impact of phenotypic diversity within the infecting bacterial population, we will map cell wall lipid variation among 140 Mtb strains among TB patients from Masiphulemele, South Africa. The resulting lipid map will describe variations in lipid composition among Mtb strains transmitting in community. From a biological perspective, Mtb’s lipid envelope forms the primary interface with the host and is therefore a direct and ongoing biochemical target of evolutionary selection. This project aims to reveal the previously undescribed chemical diversity and lipid products that have arisen as a consequence of host- and drug-derived clinical pressure. Using organism wide lipid profiling and genome wide sequencing, we have identified 42 lipid-gene pairs that dominate in Mtb strain variance, as well as 1150 lipid species overexpressed in virulent Mtb and 250 lipids selectively expressed at the host interface. Preliminary data support our ability to then link these lipids to specific bacterial genes, even when prior to knowledge of the metabolite’s structure or a gene’s function is lacking. CRISPR interference strategies will then establish causal linkages between genes of unknown function and newly discovered lipids. We will further test lipid deficient strains in collaborative cross mice to reveal specific roles of newly identified lipids in Mtb virulence. These discovery studies will identify biologically important lipids that determine key outcomes in virulence, the host interface and Mtb survival in vivo, supporting new approaches for tuberculosis diagnosis and treatment.

项目1。在人类宿主选择下进行结核分枝杆菌的研究，以鉴定病毒和屏障脂质 项目负责人：D。BranchMoody 共同评估者：Kyu Rhee，Jacob Mayfield 合作调查人员：Adriaan Minnaard（Core C），Jeremy Rock（核心D），Clare Smith（核心E） 抽象的 比较基因组学已成为跟踪结核病（TB）流行的主要范式， 了解结核分枝杆菌（MTB）病毒并开发新药和诊断。 相比之下，分枝杆菌代谢已被视为所有临床MTB菌株的不变特征。通过 在84种患者衍生的MTB菌株中，约有10,000个脂质的比较代谢组分析，我们发现 MTB的病理脂质信封显示出可识别的菌株差异模式 人口。为了确定表型多样性在感染细菌种群中的影响， 我们将在南部Masiphulemele的结核病患者中绘制140 MTB菌株之间的细胞壁脂质变化 非洲。由此产生的脂质图将描述MTB菌株在传播中脂质组成的变化 社区。从生物学的角度来看，MTB的脂质信封形成了与宿主的主要接口，并且 因此，进化选择的直接和持续的生化靶标。该项目旨在揭示 以前未描述的化学多样性和由于宿主和 药物衍生的临床压力。使用生物宽的脂质分析和基因组广泛的测序，我们有 确定了在MTB应变方差中占主导地位的42对脂质 - 基因对，以及1150种脂质物种过表达 在有毒的MTB和250个脂质中，在主机界面有选择地表达。初步数据支持我们的能力 然后，即使在知道代谢物的结构或 缺乏基因的功能。然后，CRISPR干扰策略将建立基因之间的因果关系 未知功能和新发现的脂质。我们将进一步测试合作十字架中的脂质缺陷菌株 小鼠揭示新鉴定的脂质在MTB病毒中的特定作用。这些发现研究将确定 生物学上重要的脂质，这些脂质确定病毒的关键结果，宿主界面和MTB存活率 体内，支持结核病诊断和治疗的新方法。