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.

项目概要 脑膜炎奈瑟菌是流行性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，高达 20% 的此类感染幸存者表现出 由于严重的神经炎症（脑膜炎的标志）导致永久性中枢神经系统缺陷。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发挥着关键作用 并在使用各种细胞表面和细胞识别保守的脑膜炎奈瑟氏球菌基序后这样做 膜相关模式识别受体（PPR）。此外，炎症的产生 神经胶质细胞在识别病原体相关分子模式（PAMP）后产生的介质可以发挥作用 作为宿主环境线索，指导细菌转录组的变化以促进进一步定殖 和毒力。例如，奈瑟菌表达和/或释放脂寡糖（LOS）和 肽聚糖（PGN）刺激宿主细胞产生炎症介质，这些细菌可以改变 LOS 的脂质 A 成分并释放不同数量/分布的 PGN 片段，这些片段已被 被证明可以影响非中枢神经系统细胞类型中的宿主细胞识别和反应。有趣的是，N. 据报道，脑膜炎球菌可以结合并输入宿主细胞因子，然后驱动基因表达的变化， 表明细胞因子反应可作为促进脑膜炎奈瑟氏球菌毒力的环境线索。到 日期，特定 LOS 修饰和 PGN 片段释放对神经胶质识别和反应的影响 尚未确定。因此，这项 R03 试点研究将开始解决 N. 脑膜炎球菌 PAMP 启动胶质细胞免疫反应，进而反馈调节细菌基因 表达进一步加剧感染。这些试点研究是剖析这一问题的重要的第一步。 脑膜炎奈瑟氏球菌和神经胶质细胞之间的密切关系是有害疾病发展的基础 神经炎症，将为未来的综合研究提供坚实的基础。