Bioactivities of pneumococcal cell wall in neuropathogenesis

项目摘要/摘要 以肺炎球菌为模型，我们的实验室揭示了肺炎的生化基础的许多特征。 对大脑中细菌的炎症反应。肺炎球菌是如何在血脑中传播的 屏障与其他脑膜病原体相同。我们确定了神经元是如何在 感染，揭示了细胞壁/TLR2在宿主损伤中的作用。这一重大发现 应用是在母体/胎儿界面开辟了一个新的发病机制领域，它将 细胞壁/TLR2在大脑中作用的新方面。我们已经确定了细胞壁，一种普遍存在的 病原体相关分子模式，在怀孕小鼠的血液中循环并穿越 胎盘进入胎儿大脑。胎儿神经元的反应不是很好地表征了炎症和 神经细胞的死亡发生在出生后的环境中，但恰恰相反：神经增殖没有炎症。 这种反应涉及两种新的细胞壁活动：1)诱导细胞增殖 通过TLR2的炎症信号，以及2)胚胎大脑解剖结构的重塑和 后天行为。对这一新生物学的细节的理解，将在这里进行研究 应用，既代表了新的细菌致病机理，也是一条具有很大潜力的有形途径 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。 架构，并定义胚胎发育中神经增殖的窗口。在目标2中，我们将描述 由细胞壁启动的诱导神经增殖的信号级联反应，包括通过TLR2和New PI3激酶的来源和神经转录因子FoxG1的诱导。这将把先天联系起来 核转录因子的免疫受体首次出现。目标3将决定细胞壁如何 在治疗母体脓毒症的过程中释放的药物重现了在 母亲的产前IV细胞壁暴露。我们将定义对出生后行为的后果 胎儿期神经增殖。

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.