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

• 批准号: 9237777
• 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
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-11-04 至 2021-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9237777
• 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; Postnatal Neuronal Death; Pregnancy; Receptor Cell; Research; Role; Sepsis; Signal Transduction; Source; Specificity; Steroids; Streptococcus pneumoniae; TLR2 gene; Teichoic Acids; Testing; Time; Tissues; autism spectrum disorder; behavior test; brain abnormalities; brain morphology; fetal; in utero; mouse model; neurodevelopment; neuron apoptosis; novel; pathogen; postnatal; pregnant; prenatal; pup; response; transcription factor

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.

项目摘要/摘要 我们的实验室使用肺炎球菌作为模型，揭示了许多生化基础的特征 对大脑细菌的炎症反应。肺炎肺部流量如何遍布整个血脑 障碍是由其他脑膜病原体共享的。我们确定神经元如何因凋亡而死亡 感染并揭示了细胞壁/TLR2在宿主损伤中的作用。这一点的重要发现 应用是在母亲/胎儿界面处的新发病机理的开放，该区域将告知 细胞壁/TLR2的新方面在大脑中影响。我们已经确定了细胞壁，一种通用 病原体相关的分子模式，在怀孕小鼠的血液中循环并遍历 胎盘到胎儿大脑。胎儿神经元的反应不是炎症的特征， 产后环境的神经元死亡，但恰恰相反：无炎症的神经增生。 这种反应涉及两个细胞壁的新活动：1）诱导细胞增殖而没有 通过TLR2的炎症信号传导，2）重塑胚胎脑解剖结构和变化 产后行为。对这种新生物学细节的理解，将在此研究 应用既代表新的细菌发病机理，又代表了有形的高潜力的途径 医疗影响。 我们建议在AIM 1中对大脑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生的窗口。在AIM 2中，我们将描述 细胞壁引发的信号传导级联反应诱导神经增生，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 首次对核转录因子免疫受体。 AIM 3将决定细胞壁 在孕产妇败血症治疗期间发行，概括了在模型中看到的神经增生 母亲的产前IV细胞壁暴露。我们将定义对产后行为的后果 产前神经增生。