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.

项目总结/摘要 以肺炎球菌为模型，我们的实验室揭示了肺炎球菌的生化基础的许多特征， 对细菌的炎症反应肺炎球菌是如何穿过血脑的 屏障被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/TLR 2在宿主损伤中的作用。这一重要发现 应用是在母体/胎儿界面打开一个新的发病机制领域， 细胞壁/TLR 2在大脑中作用的新方面。我们已经确定细胞壁，一种普遍的 病原体相关的分子模式，在怀孕小鼠的血流中循环，并穿过 胎盘到胎儿大脑胎儿神经元的反应不是特征性的炎症， 出生后环境中的神经元死亡，但恰恰相反：无炎症的神经增殖。 这种反应涉及细胞壁的两种新活动：1）诱导细胞增殖， 通过TLR 2的炎症信号传导，和2）胚胎脑解剖结构的重塑和 产后行为。对这种新生物学的细节的理解，将在这一领域进行研究。 应用，既代表了新的细菌发病机制，也代表了有形的高潜力途径 医学影响。 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 结构和定义胚胎发育中神经增殖的窗口。在目标2中， 由细胞壁引发的信号级联反应诱导神经增殖，包括通过TLR 2和新的 PI 3激酶的来源和神经元转录因子FoxG 1的诱导。这将连接先天 免疫受体的核转录因子的第一次。目标3将确定细胞壁 在母体败血症治疗过程中释放的， 产前IV细胞壁暴露的母亲。我们将定义产后行为的后果， 产前神经增殖