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

项目摘要 脑膜炎奈瑟氏菌是脑膜炎双球菌脑膜炎的病原体，可导致流行性脑膜炎。 未经治疗的患者死亡率高达50%。此外，高达20%的此类感染幸存者表现出 由于严重的神经炎症而导致的永久性中枢神经系统缺陷，这是脑膜炎的一个特征。现在人们意识到， 驻留的胶质细胞，包括小胶质细胞和星形胶质细胞，在启动这种破坏性炎症中起着关键作用。 在识别保守的脑膜炎奈瑟氏菌基序之后，使用细胞表面和 膜相关模式识别受体(PPR)。此外，炎症性物质的产生 神经胶质细胞识别病原体相关分子模式(PAMPs)后的介体可以发挥作用 作为宿主环境线索，指示细菌转录组的变化以促进进一步的定居 和致命性。例如，奈瑟氏菌表达和/或释放脂低聚糖(LOS)和 肽聚糖(PGN)刺激宿主细胞产生炎症介质，这些细菌可以修改 脂类A组分丢失并释放不同量/谱PGN片段 在非中枢神经系统细胞类型中被证明影响宿主细胞的识别和反应。耐人寻味的是，N. 据报道，脑膜炎可以结合和输入宿主细胞因子，然后驱动基因表达的变化， 这表明细胞因子反应是促进脑膜炎奈瑟氏菌毒力的环境线索。至 特异性LOS修饰和PGN片段释放对神经胶质细胞识别和反应的影响 还没有确定。因此，这项R03先导研究将开始解决N。 脑膜炎PAMPs启动神经胶质免疫反应，进而反馈调节细菌基因 表达会进一步加剧感染。这些先导性研究是解剖 脑膜炎奈瑟氏菌与神经胶质细胞之间的密切关系是有害脑膜炎发生的基础 并将为今后的全面研究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.