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

神经胶质细胞对脑膜炎奈瑟菌炎症反应的分子机制：一项初步研究

• 批准号: 10452116
• 负责人: Morgan Brittany Johnson
• 金额: $ 7.55万
• 依托单位: UNIVERSITY OF NORTH CAROLINA CHARLOTTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-15 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10452116
• 关键词: Address; Anti-Inflammatory Agents; Astrocytes; Bacteria; Bacterial Genes; Binding; Biological Assay; Biological Response Modifiers; Brain Injuries; Cell Death; Cell membrane; Cell surface; Cells; Cues; Data; Development; Disease; Enzyme-Linked Immunosorbent Assay; Epidemic; Exposure to; Fatality rate; Feedback; Future; Gene Expression; Gene Expression Profiling; Generations; Immune response; Individual; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Investigation; Knowledge; Lead; Lipid A; Mediating; Meningitis; Meningococcal Infections; Meningococcal meningitis; Microglia; Modification; Molecular; Morbidity - disease rate; Neisseria; Neisseria meningitidis; Neuroglia; Neurons; Pathogenesis; Patients; Pattern; Pattern recognition receptor; Peptidoglycan; Pilot Projects; Play; Production; Reporting; Solid; Surface; Survivors; Testing; Vaccines; Variant; Virulence; cell type; cytokine; disability; experimental study; global health; hearing impairment; immunogenic; immunogenicity; in vivo; innovation; lipooligosaccharide; mortality; neuroinflammation; neuron loss; neurotoxic; new therapeutic target; novel therapeutics; pathogen; pathogenic bacteria; response; transcriptome; universal vaccine

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.

项目摘要 奈瑟氏菌脑膜炎是脑膜炎球菌性脑膜炎的病因，它可能导致流行病 未经治疗的患者的死亡率高达50％。此外，多达20％的感染幸存者表明 由于严重的神经炎症，永久性中枢神经系统缺陷，这是脑膜炎的标志。现在感谢 居民神经胶质细胞，包括小胶质细胞和星形胶质细胞，在发起这种破坏性炎症中起着关键作用 并在使用各种细胞表面和 膜相关的模式识别受体（PPRS）。此外，炎症的产生 在识别病原体相关的分子模式（PAMP）之后，通过神经胶质细胞进行介质可以使用 作为直接变化细菌转录组以促进进一步定殖的宿主环境线索 和毒力。例如，奈瑟氏菌表达和/或脂肪糖（LOS）和/或释放 肽聚糖（PGN）刺激炎症介质的宿主细胞产生，这些细菌可以改变 LOS的脂质成分，并释放PGN片段的不同量/轮廓 证明会影响非CNS细胞类型中的宿主细胞识别和反应。有趣的是，N。 据报道，脑膜炎结合和进口宿主细胞因子，然后驱动基因表达的变化， 表明细胞因子反应是促进脑膜炎脑毒性的环境线索。到 日期，特定的LOS修饰和PGN片段释放对神经胶质识别和响应的影响 尚未确定。因此，这项R03试点研究将开始解决N. N. 脑膜炎pamps发起了神经胶质免疫反应，反过来反馈以调节细菌基因 表达进一步加剧感染。这些试点研究是剖析 脑膜炎链球菌与神经胶质细胞之间的亲密关系，这些细胞是有害发展的基础的 神经炎症，将为将来的全面调查提供扎实的理由。