Bioactivities of pneumococcal cell wall in neuropathogenesis

以肺炎球菌为模型，我们的实验室揭示了许多生化基础的特征。 对大脑中细菌的炎症反应。这个应用程序的重要发现是 在母体/胎儿界面打开一个新的致病区域，这将为新发现的 细胞壁/TLR2在大脑中作为一种形态因子发挥作用。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)通过TLR2诱导细胞增殖，而不是 炎症信号，以及2)胚胎大脑解剖结构的重建和出生后的变化 行为。我们将进一步确定这些发现与使用有机化合物的人脑的相关性。 对这种新生物学的细节的理解，将在本申请中进行研究，代表 这既是一种新的细菌发病机制，也是一种具有实际医疗影响的高潜力途径。vbl.使用 单细胞空间RNAseq和基因敲除动物模型，我们建议识别信号级联 由细胞壁启动，以调节大脑结构，包括确定TLR2/6、TLR2/6和TLR2/6之间的联系 神经元纤毛信号转导节点和神经转录因子FoxG1。这将连接到 先天免疫受体首次与核转录因子结合并定义了一种新的活性 TLRs作为形态生物质。兰多自噬途径的参与将被描述为一个细胞 与认知功能缺陷相关的壁运输/移除途径。

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.