Molecular mechanisms underlying glial inflammatory responses to Neisseria meningitidis: A pilot study

项目摘要 脑膜炎奈瑟菌是脑膜炎球菌性脑膜炎的病原体，可导致流行病， 未经治疗的患者死亡率高达50%。此外，多达20%的此类感染幸存者显示， 由于严重的神经炎症导致的永久性CNS缺陷，这是脑膜炎的标志。现在人们认识到， 常驻神经胶质细胞，包括小胶质细胞和星形胶质细胞，在引发这种破坏性炎症中起关键作用 并在识别保守的N.脑膜炎病毒基序，使用细胞表面的分类， 膜相关模式识别受体（PPRs）。此外，炎症的产生 神经胶质细胞识别病原体相关分子模式（PAMPs）后， 作为宿主环境线索，指导细菌转录组的变化以促进进一步的定殖 和毒性。例如，奈瑟氏菌属表达和/或释放脂寡糖（LOS）和 肽聚糖（PGN）刺激宿主细胞产生炎症介质，这些细菌可以修饰 LOS的脂质A组分，并释放不同量/谱的PGN片段， 证实影响非CNS细胞类型中的宿主细胞识别和应答。有趣的是，N。 据报道脑膜炎结合并输入宿主细胞因子，然后驱动基因表达的变化， 表明细胞因子反应作为环境线索促进N.脑膜炎毒力到 具体LOS修饰和PGN片段释放对胶质细胞识别和反应的影响 尚未确定。因此，本R 03初步研究将开始，以解决的假设，N。 脑膜炎PAMPs启动神经胶质免疫反应，反过来，反馈调节细菌基因 表达，以进一步加剧感染。这些试验性研究是剖析 N之间的亲密关系。脑膜炎和神经胶质细胞，这些细胞是有害的 神经炎症，并将为未来的全面调查提供坚实的理论基础。

Project Summary Neisseria meningitidis is the causative agent of meningococcal meningitis, which can lead to epidemics with a fatality rate of up to 50% in untreated patients. In addition, up to 20% of survivors of such infections show permanent CNS deficits due to severe neuroinflammation, a hallmark of meningitis. It is now appreciated that resident glial cells, including microglia and astrocytes, play a key role in initiating such damaging inflammation and do so following the recognition of conserved N. meningitidis motifs using an assortment of cell surface and membrane-associated pattern recognition receptors (PPRs). Furthermore, the production of inflammatory mediators by glial cells following the recognition of pathogen associated molecular patterns (PAMPs) can serve as host environmental cues that direct changes in the bacterial transcriptome to promote further colonization and virulence. For example, Neisseria expression and/or release of the lipooligosaccharide (LOS) and peptidoglycan (PGN) stimulates host cell production of inflammatory mediators, and these bacteria can modify the lipid A component of LOS and release different amounts/profiles of PGN fragments that have been demonstrated to influence host cell recognition and responses in non-CNS cell types. Intriguingly, N. meningitidis has been reported to bind and import host cytokines that then drive changes in gene expression, suggesting that cytokine responses serve as environmental cues to promote N. meningitidis virulence. To date, the effect of specific LOS modifications and PGN fragment release on glial recognition and responses has not been determined. Accordingly, this R03 pilot study will begin to address the hypothesis that N. meningitidis PAMPs initiate glial immune responses that, in turn, feedback to regulate bacterial gene expression to further exacerbate infection. These pilot studies are an essential first step in dissecting the intimate relationship between N. meningitidis and glial cells that underlies the development of detrimental neuroinflammation and will provide a solid rationale for future comprehensive investigations.