Bioactivities of pneumococcal cell wall in neuropathogenesis

肺炎球菌细胞壁在神经发病机制中的生物活性

基本信息

批准号：
10569107
负责人：
Elaine I Tuomanen
金额：
$ 45.5万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-11-04 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10569107
关键词：
Affect Amyloid Anatomy Animal Model Architecture Area Autophagocytosis Bacteria Behavior Binding Biochemical Biology Birth Blood Circulation Brain Cell Communication Cell Cycle Kinetics Cell Death Cell Proliferation Cell Wall Cell surface Cells Cilia Circulation Data Defect Development Dimensions Drosophila genus Embryo Equilibrium Evolution Excision Exposure to FOXG1B gene Fetus Functional disorder Gram-Positive Bacterial Infections Homeostasis Human Immune Immune signaling Immunologic Receptors Individual Infection Inflammation Inflammatory Inflammatory Response Injury Innate Immune Response Link Measures Medical Meningitis Modeling Modification Molecular Morphogenesis Mus Natural Immunity Neurons Neuropathogenesis Nuclear Organ Organoids Pathogenesis Pathway interactions Pattern Placenta Pneumonia Publications Recycling Regulation Role SHH gene Sensory Sepsis Shapes Signal Induction Signal Pathway Signal Transduction Sonic Hedgehog Pathway Streptococcus pneumoniae Structure Subcellular Anatomy TLR2 gene Testing Time Work brain abnormalities cell type cognitive function experimental study fetal fly forkhead protein in utero innovation knockout animal model organism morphogens mouse model neurodevelopment neurogenesis neuroprotection novel pathogen pathogenic bacteria postnatal postnatal neuronal death pregnant programs pup receptor recycling response tissue injury trafficking transcription factor transcriptome sequencing

项目摘要

Using the pneumococcus as a model, our lab has revealed many features of the biochemical basis of the inflammatory response to bacteria in the brain. The important discovery of this application is the opening of a new area of pathogenesis at the maternal/fetal interface that will inform newly discovered cell wall/TLR2 effects as a morphogen in the brain. We have determined that cell wall, a universal pathogen associated molecular pattern, circulates in the bloodstream of pregnant mice and traverses the placenta to the fetal brain. The response of fetal neurons is not the well characterized inflammation and neuronal death of the postnatal setting but the exact opposite: neuroproliferation without inflammation. This response involves two new activities of cell wall: 1) induction of cell proliferation via TLR2 without inflammatory signaling, and 2) remodeling of embryonic brain anatomy and changes in postnatal behavior. We will further determine the relevance of these findings to the human brain using organoids. An understanding of the details of this new biology, to be investigated in this application, represents both novel bacterial pathogenesis and an avenue of high potential for tangible medical impact. Using single cell spatial RNASeq and knock out animal models, we propose to identify the signaling cascade initiated by cell wall to modulate brain structure, including determining the links between TLR2/6, the signaling node of the neuronal cilium and the neuronal transcription factor FoxG1. This will connect innate immune receptors to nuclear transcription factors for the first time and define a new activity of TLRs as morphogens. The involvement of the LANDO autophagy pathway will be characterized as a cell wall trafficking/removal pathway associated with defects in cognitive function.

我们的实验室以肺炎球菌为模型，揭示了肺炎球菌生化基础的许多特征对大脑中细菌的炎症反应。该应用的重要发现是在母体/胎儿界面开辟一个新的发病机制领域，这将为新发现提供信息细胞壁/TLR2 作为大脑中的形态发生素发挥作用。我们已经确定细胞壁是一种普遍存在的物质病原体相关的分子模式，在怀孕小鼠的血液中循环并穿过胎盘到胎儿大脑。胎儿神经元的反应并不是明确表征的炎症和产后环境中的神经元死亡，但恰恰相反：没有炎症的神经增殖。这种反应涉及细胞壁的两种新活性：1）通过 TLR2 诱导细胞增殖，而无需炎症信号传导，2) 胚胎大脑解剖结构的重塑和产后变化行为。我们将使用类器官进一步确定这些发现与人脑的相关性。了解本申请中要研究的这种新生物学的细节代表既是新颖的细菌发病机制，又是产生切实医学影响的巨大潜力的途径。使用单细胞空间RNASeq和敲除动物模型，我们建议鉴定信号级联由细胞壁发起调节大脑结构，包括确定 TLR2/6、TLR2/6 之间的联系神经元纤毛和神经元转录因子 FoxG1 的信号传导节点。这将连接首次发现核转录因子的先天免疫受体，并定义了一种新的活性 TLR 作为形态发生素。 LANDO自噬途径的参与将被表征为细胞与认知功能缺陷相关的壁运输/去除途径。