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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）

基本信息

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
项目类别：
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

项目摘要

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。结核分枝杆菌在人类宿主选择下的毒力鉴定和屏障脂质的研究