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

• 批准号: 10651853
• 负责人: DAVID Branch MOODY
• 金额: $ 62.28万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 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/10651853
• 关键词: Acceleration; 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; Macrophage; 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; chemical synthesis; comparative; comparative genomics; experience; experimental study; forward genetics; gene discovery; gene function; genetic approach; in vivo; inhibitor; insight; invention; lipidome; lipidomics; metabolomics; mycobacterial; novel strategies; overexpression; pathogen; pathogenic bacteria; prenyl; rapid detection; receptor; response; reverse genetics; selective expression; success; tool; transcriptomics; translational study

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.

项目概要 主要细菌病原体中脂质毒力因子的化学生物学发现 几十年来，对细菌毒力原因的研究一直集中在基因而不是代谢物上。 遗传方法已取得广泛成功，现代传染病研究依赖于 基本上是在主要病原体的基因组图谱上。由于缺乏全生物化学物质 生物学工具中，细菌脂质尚未对其毒力作用进行系统测试，尽管脂质 是与人类宿主的主要界面，它们控制营养流动并触发宿主免疫 回复。我们发明了一种用于脂质分析的质谱平台，可以检测样品中几乎所有可电离的脂质。 2小时内细菌细胞。结核分枝杆菌和肠沙门氏菌血清型实验 伤寒现在为普遍认识提供了明确的证据，即世界上许多（也许是大多数）脂质 细菌病原体，目前未知为命名化合物。基于毒力鉴定的成功 两种具有世界意义的主要病原体的因素，我们将采用已知的化学生物学方法 作为前瞻性脂质组学。具体来说，我们将使用整个生物体质谱分析来发现 在有毒细菌中选择性表达且在现有脂质目录中未知的脂质。然后，我们 将化学合成毒力相关的脂质并将它们与其生物合成基因连接起来以进行删除 使用反向遗传方法在细菌中。使用缺乏定义的转基因细菌 脂质，我们将确定毒力脂质在感染过程中的作用。使用与天然相同的合成脂质，我们 将确定泡沫巨噬细胞生成的细胞机制并识别免疫受体 介导宿主反应。我们将根据以下内容创建主要革兰氏阴性病原体组的脂质图 患者菌株建立了被忽视的细菌毒力化学生物学领域。这些基本的和 转化研究将支持开发新的脂质组学方法来诊断和治疗 重大传染病的治疗。

项目成果

Nucleocapsid protein accumulates in renal tubular epithelium of a post-COVID-19 patient.

核衣壳蛋白在 COVID-19 后患者的肾小管上皮中积聚。

• 发表时间: 2023-12-12
• 影响因子: 3.7
• 作者: Grootemaat, Anita E;Wiersma, Niek;van der Niet, Sanne;Schimmel, Irene M;Florquin, Sandrine;Reits, Eric A;Miller, Sara E;van der Wel, Nicole N
• 通讯作者: van der Wel, Nicole N