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：
10053312
负责人：
Elaine I Tuomanen
金额：
$ 44.88万
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 2022-02-07
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10053312
关键词：
1-Phosphatidylinositol 3-Kinase Address Affect Anatomy Animal Model Animals Antibiotics Apoptosis Apoptotic Architecture Area Bacteremia Bacteria Bacterial Infections Behavior Behavioral Binding Biochemical Biology Birth Blood - brain barrier anatomy Blood Circulation Brain Cell Culture Techniques Cell Proliferation Cell Wall Cell division Cell physiology Cells Clinical Cognitive Complex Data Dependence Dose Embryo Embryonic Development Event FOXG1B gene Fetal Development Fetus Functional disorder Gram-Positive Bacterial Infections Hippocampus (Brain)Immune Immune signaling Immunologic Receptors In Vitro Infection Inflammation Inflammatory Inflammatory Response Injury Innate Immune Response Lead Life Link Maps Maternal-Fetal Exchange Medical Meningeal Meningitis Modeling Molecular Morphology Mothers Mus Neuroglia Neurons Neuropathogenesis Newborn Infant Nuclear Outcome Pathogenesis Pattern Pattern Recognition Peptidoglycan Phenotype Placenta Play Pneumococcal Infections Pneumonia Pregnancy Pregnant Women Receptor Cell Research Role Sepsis Signal Transduction Source Specificity Steroids Streptococcus pneumoniae TLR2 gene Teichoic Acids Testing Time autism spectrum disorder behavior test brain abnormalities brain morphology fetal in utero mouse model neurodevelopment neuron apoptosis novel pathogen postnatal postnatal neuronal death pregnant prenatal pup response tissue injury transcription factor

项目摘要

Project Summary/Abstract 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. How the pneumococcus traffics across the blood brain barrier is shared by other meningeal pathogens. We determined how neurons die by apoptosis during infection and revealed the role of cell wall/TLR2 in host damage. The important discovery of this application is the opening of a new area of pathogenesis at the maternal/fetal interface that will inform new aspects of cell wall/TLR2 effects 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 without inflammatory signaling via TLR2, and 2) remodeling of embryonic brain anatomy and changes in postnatal behavior. 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. We propose in Aim 1 to undertake detailed neuroanatomical assessment of the changes in brain architecture and define the window of neuroproliferation in embryogenesis. In Aim 2 we will characterize the signaling cascades initiated by cell wall to induce neuroproliferation, including via TLR2 and novel sources of PI3 kinase and induction of the neuronal transcription factor FoxG1. This will link innate immune receptors to nuclear transcription factors for the first time. Aim 3 will determine how cell wall released during the treatment of maternal sepsis recapitulates the neuroproliferation seen in the model of prenatal IV cell wall exposure of the mother. We will define the consequences to postnatal behavior of prenatal neuroproliferation.

项目概要/摘要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。肺炎球菌如何穿过血脑该屏障由其他脑膜病原体共享。我们确定了神经元如何通过细胞凋亡而死亡感染并揭示了细胞壁/TLR2 在宿主损伤中的作用。这一重要发现应用是在母体/胎儿界面开辟一个新的发病机制领域，这将告知细胞壁/TLR2 在大脑中的作用的新方面。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）诱导细胞增殖，而无需通过 TLR2 的炎症信号传导，以及 2）胚胎大脑解剖结构的重塑和产后行为。了解这种新生物学的细节，将在本研究中进行研究应用，既代表了新的细菌发病机制，又代表了有形的高潜力途径医疗影响。我们在目标 1 中建议对大脑的变化进行详细的神经解剖学评估结构并定义胚胎发生中神经增殖的窗口。在目标 2 中，我们将描述由细胞壁启动的信号级联诱导神经增殖，包括通过 TLR2 和新型 PI3 激酶的来源和神经元转录因子 FoxG1 的诱导。这将链接先天首次发现核转录因子的免疫受体。目标 3 将确定细胞壁如何在治疗孕产妇脓毒症期间释放的物质重现了模型中所见的神经增殖母亲产前 IV 细胞壁暴露。我们将定义对产后行为的后果产前神经增殖。