Metabolic modulation of Fusobacterium nucleatum virulence

具核梭杆菌毒力的代谢调节

• 批准号: 10681729
• 负责人: Hung Ton-That
• 金额: $ 21.25万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10681729
• 关键词: Acetaldehyde; Acetyl Coenzyme A; Affect; Amniotic Fluid; Anaerobic Bacteria; Anti-Infective Agents; Applications Grants; Bacterial Adhesins; Binding; Biochemistry; Bioinformatics; Carbon; Catabolism; Cell membrane; Cells; Chorionic villi; Code; Colon; Colorectal Cancer; Communities; Data; Dental Plaque; Development; Disease; Distal; Encapsulated; Environment; Environmental Risk Factor; Enzymes; Escherichia coli; Ethanolamine Ammonia-Lyase; Ethanolamines; Fetal Development; Fetal Tissues; Fetus; First Pregnancy Trimester; Functional disorder; Fusobacterium nucleatum; Future; Gal-GalNAc; Gene Cluster; Genes; Genetic; Genetic Determinism; Goals; Growth; Hematogenous; Human; Hypothetical Protein; Immunity; In Vitro; Infection; Inflammation; Knowledge; Link; Mediating; Metabolic; Metabolism; Microbial Biofilms; Molecular; Mothers; Mouth Diseases; Mus; Nitrogen; Odontogenesis; Organ; Organelles; Organism; Parents; Pathogenesis; Pathogenicity; Phosphatidylethanolamine; Phospholipids; Placenta; Play; Pregnancy Complications; Premature Birth; Proteins; Reporting; Role; Salmonella; Signal Transduction; Signaling Molecule; Site; Source; Structural Protein; Survival Rate; System; Testing; Third Pregnancy Trimester; Time; Toxic effect; Umbilical Cord Blood; Virulence; Virulence Factors; Work; adverse pregnancy outcome; comparative; differential expression; fetal; genetic approach; in vivo; in vivo Model; malignant breast neoplasm; mouse model; mutant; oral biofilm; pathogen; pathogenic bacteria; prevent; public health relevance; pup; response; stillbirth; symbiont; therapeutic target; transcriptome sequencing

PROJECT SUMMARY Fusobacterium nucleatum, a Gram-negative anaerobe that plays a key role in the development of oral biofilms, or dental plaque, has the remarkable ability to escape host immunity and spread to extraoral sites, including placenta and colon, where it is associated with significant diseases such as preterm birth and colorectal cancer. To date, we have a poor understanding of the mechanisms of virulence and disease by F. nucleatum, and the environmental factors in the extraoral sites that potentially affect the virulence potential of this pathogen. Considering that ethanolamine (EA) – an important source of carbon/nitrogen and energy, and a signaling molecule for some bacterial pathogens – is abundant in placenta during fetal development, we aim to test the central hypothesis that regulated EA metabolism via a specialized organelle, bacterial microcompartment (BMC), modulates the virulence potential of F. nucleatum. This hypothesis is based on our compelling preliminary data showing that environmental EA stimulates BMC formation and expression of EA utilization genes, and that blockage in EA catabolism alters the pathogenicity of F. nucleatum. The major goal of this application is to examine how BMC-mediated EA utilization affects fusobacterial virulence (Aim 1) and how blockage in EA catabolism modulates fusobacterial pathogenicity (Aim 2). The results generated from our studies will not only provide important knowledge regarding the pathophysiology of F. nucleatum and promising therapeutic targets, but also have potential to advance the broad field of host-pathogen interactions.

项目摘要 具核梭杆菌是一种革兰氏阴性厌氧菌，在口腔生物膜的形成中发挥关键作用， 或牙菌斑，具有逃避宿主免疫并扩散到口外部位的显著能力，包括 胎盘和结肠，在那里它与早产和结肠直肠癌等重大疾病有关。 迄今为止，我们对F.核质， 可能影响该病原体毒力潜力的口外部位环境因素。 考虑到乙醇胺（EA）-碳/氮和能量的重要来源，以及信号传导， 一些细菌病原体的分子-在胎儿发育期间胎盘中丰富，我们的目的是测试 一个中心假设，通过一个专门的细胞器，细菌微区室（BMC）， 调节F.具核的这个假设是基于我们令人信服的初步数据 表明环境EA刺激BMC形成和EA利用基因的表达， 阻断EA催化剂可改变F.具核的此应用程序的主要目标是 研究BMC介导的EA利用如何影响梭菌的毒力（目的1）以及EA的阻断如何影响梭菌的毒力（目的1）。 catalysts调节梭菌的致病性（目的2）。我们的研究成果不仅将 提供有关F.核质和有前景的治疗靶点， 而且有潜力推进宿主-病原体相互作用的广泛领域。