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Chemical Biological Discovery of Lipid Virulence Factors in the Major Bacterial Pathogens

主要细菌病原体中脂质毒力因子的化学生物学发现

基本信息

批准号：
10518252
负责人：
DAVID Branch MOODY
金额：
$ 64.25万
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：
2022
资助国家：
美国
起止时间：
2022-06-22 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10518252
关键词：
Address Autophagocytosis Bacteria Bacterial Chromosomes Biological Biological Process Biology Catalogs Cell model Cells Cellular Assay Chemical Structure Chemicals Chromosome Mapping Communicable Diseases Cord Factors Data Databases Detection Development Diagnosis Disease Enteral Environment Evolution Feedback Foamy Macrophage Functional disorder Gene Deletion Generations Genes Genomics Genus Mycobacterium Gram-Negative Bacteria Hour Human Immune response Immunologic Receptors Infection Infectious Diseases Research Laboratories Link Lipids Literature Location Lysosomes Maps Mass Spectrum Analysis Measures Mediating Membrane Methods Modernization Molecular Mus Mycobacterium tuberculosis Names Nature Nucleosides Nutrient Organism Patients Phenotype Phospholipids Process Production Proteins Proteomics Role Salmonella Salmonella enterica Salmonella typhi Science Signal Transduction Study Section System T cell response Testing Transcript Virulence Virulence Factors Virulent Whole Organism base comparative comparative genomics experience experimental study forward genetics gene discovery gene function genetic approach in vivo inhibitor insight lipidome lipidomics macrophage metabolomics mycobacterial novel strategies overexpression pathogen pathogenic bacteria prenyl receptor response reverse genetics selective expression success tool transcriptomics translational study

项目摘要

Project Summary Chemical Biological Discovery of Lipid Virulence Factors in the Major Bacterial Pathogens For decades, the search for the causes of bacterial virulence has focused on genes rather than metabolites. Genetic approaches have been broadly successful, and modern infectious disease research relies fundamentally on genomic maps of the major pathogens. Owing to the lack of whole-organism chemical biology tools, bacterial lipids have not been systematically tested for their roles in virulence, even though lipids are the primary interface with the human host, where they control nutrient flow and trigger host immune response. We invented a mass spectrometry platform for lipid profiling to detect nearly all ionizable lipids in a bacterial cell within 2 hours. Experiments on Mycobacterium tuberculosis and Salmonella enterica serovar Typhi now provide clear evidence for the general insight that many, perhaps the majority, of lipids in the world's bacterial pathogens, are currently unknown as named compounds. Based on successes in identifying virulence factors in two major pathogens of worldwide significance, we will carry out a chemical biology approach known as forward lipidomics. Specifically, we will use whole organism mass spectrometry profiling to discover the lipids that are selectively expressed in virulent bacteria and are unknown in existing lipid catalogs. Then, we will chemically synthesize the virulence associated lipids and link them to their biosynthetic genes for deletion in bacteria using reverse genetic approaches. Using genetically modified bacteria that are deficient in defined lipids, we will determine the roles of virulence lipids during infection. Using nature identical synthetic lipids, we will determine the cellular mechanisms of generation of foamy macrophages and identify immune receptors that mediate host response. We will create lipid maps of the major Gram negative pathogen groups based on patient strains to build the overlooked field of chemical biology of bacterial virulence. These basic and translational studies will support the development new forward lipidomics approaches to the diagnosis and treatment of major infectious diseases.

项目摘要主要致病菌中脂类毒力因子的化学生物学发现几十年来，寻找细菌毒力的原因一直集中在基因上，而不是代谢物上。基因方法在很大程度上是成功的，现代传染病研究依靠基本上取决于主要病原体的基因组图谱。由于缺乏全生物体的化学物质生物学工具，细菌脂类还没有系统地测试它们在毒力中的作用，即使脂类是与人类宿主的主要接口，在那里它们控制营养流动并触发宿主免疫回应。我们发明了一种用于脂类分析的质谱学平台，可以检测几乎所有可电离的脂类细菌细胞在2小时内。结核分枝杆菌和肠道沙门氏菌血清型的实验研究伤寒现在为普遍的洞察力提供了明确的证据，即世界上许多，也许是大多数的脂质细菌病原体，目前作为命名化合物尚不为人所知。基于在鉴定毒力方面的成功在两种具有世界意义的主要病原体因素中，我们将开展一种已知的化学生物学方法这是一种前沿性的脂质组学。具体地说，我们将使用整个生物体的质谱图来发现在致病细菌中选择性表达的脂类，在现有的脂类目录中未知。然后，我们将化学合成与毒力相关的脂类，并将它们与其生物合成基因联系起来进行删除在使用反向遗传方法的细菌中。使用定义有缺陷的转基因细菌脂类，我们将确定毒力类脂在感染过程中的作用。使用天然相同的合成脂类，我们将确定泡沫巨噬细胞产生的细胞机制并识别免疫受体这是宿主反应的中介。我们将根据以下内容创建主要革兰氏阴性病原菌群的脂谱患者菌株构建了被忽视的细菌毒力化学生物学领域。这些基本的和翻译研究将支持开发新的正向脂组学方法来诊断和重大传染病的救治。