RIG-I as a therapeutic target for bacterial CNS infection: A pilot study

RIG-I 作为细菌中枢神经系统感染的治疗靶点：一项初步研究

基本信息

批准号：
10303500
负责人：
Morgan Brittany Johnson
金额：
$ 15.1万
依托单位：
UNIVERSITY OF NORTH CAROLINA CHARLOTTE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10303500
关键词：
Agonist Anti-Bacterial Agents Antibacterial Response Astrocytes Bacterial Infections Bacterial Meningitis Biological Assay Biological Response Modifiers Brain Cause of Death Cell surface Cells Central Nervous System Bacterial Infections Cessation of life Clinical Data Enzyme-Linked Immunosorbent Assay Evaluation Exposure to Future Genes Host Defense Hour Human Imaging Techniques Immune Immune response Immunity In Vitro Infection Infectious Agent Inflammatory Response Interferons Knowledge Mediating Meningitis Meningoencephalitis Microglia Neuraxis Neuroglia Neurologic Deficit New Agents Nucleic Acids Pattern recognition receptor Peripheral Pharmacology Pilot Projects Play Production Publishing Regulation Role Shapes Small Interfering RNA Solid Surface Testing Therapeutic Toll-like receptors Tretinoin Viral Virus Receptors Work adaptive immune response base cell type clinically relevant defined contribution disability experimental study functional group immunoregulation in vivo inhibitor/antagonist knock-down nanoparticle neuroinflammation new therapeutic target novel nucleic acid-based therapeutics pathogen pathogenic bacteria programs prophylactic protective effect response sensor synthetic nucleic acid therapeutic target

项目摘要

Project Summary Bacterial meningitis and meningoencephalitis are serious clinical conditions that result in permanent disabilities and can even cause death within hours. It is now appreciated that resident glia, such as microglia and astrocytes, play an important role in both protective and detrimental immune responses, and such responses to bacterial infection of the central nervous system (CNS) are initiated via pattern recognition receptor (PRR)-dependent identification of pathogen motifs. Therefore, defining the mechanisms underlying glial bacterial recognition has the potential to identify novel therapeutic targets. We, and others, have shown that glial cells use a combination of cell surface and cytosolic PRRs to identify pathogen motifs. Intriguingly, while retinoic acid-inducible gene-I (RIG-I), is known to recognize viral nucleic acids, recent evidence suggests that this cytosolic PRR may play a novel role in the identification of bacterial nucleic acids. In contrast to the potentially devastating inflammatory responses that can be initiated by surface PRRs, RIG-I activation stimulates interferon production that shapes protective innate and adaptive immune responses to infection. To date, the ability of RIG-I to identify bacterial nucleic acids in glial cells thereby promoting antibacterial responses has not been explored. Our recently published data indicates RIG-I expression is upregulated in microglia following exposure to disparate clinically relevant bacterial pathogens of the CNS, and such challenge can initiate potentially protective interferon production. In this pilot R03 study, we will investigate the hypothesis that bacterial recognition via RIG-I promotes protective glial responses. Results from these pilot studies will expand our knowledge of RIG-I function and regulation in glia during bacterial challenge, and begin to evaluate the in vitro protective effects of a novel synthetic nucleic acid nanoparticle RIG-I agonist. Collectively, these pilot studies will provide a solid rationale for a future comprehensive analysis of the relative importance of RIG-I-mediated glial responses in bacterial infections of the CNS, and an in vivo examination of the therapeutic potential of novel synthetic RIG-I agonists.

项目概要细菌性脑膜炎和脑膜脑炎是严重的临床病症，可导致永久性残疾，并可甚至在数小时内导致死亡。现在人们认识到，常驻神经胶质细胞，例如小胶质细胞和星形胶质细胞，在在保护性和有害性免疫反应以及对细菌感染的反应中发挥重要作用中枢神经系统 (CNS) 通过模式识别受体 (PRR) 依赖性病原体识别启动主题。因此，定义神经胶质细菌识别的机制有可能识别新的治疗目标。我们和其他人已经证明，神经胶质细胞利用细胞表面和胞质 PRR 的组合来识别病原体基序。有趣的是，虽然已知视黄酸诱导基因-I (RIG-I) 可以识别病毒核酸最近的证据表明，这种胞质 PRR 可能在细菌核酸的鉴定中发挥新的作用酸。与表面 PRR 可能引发的潜在破坏性炎症反应相比，RIG-I 激活刺激干扰素的产生，形成对感染的保护性先天和适应性免疫反应。迄今为止，RIG-I 识别神经胶质细胞中细菌核酸从而促进抗菌反应的能力已被证实。没有被探索过。我们最近发表的数据表明，暴露后小胶质细胞中 RIG-I 的表达上调区分中枢神经系统临床相关的细菌病原体，这种挑战可以启动潜在的保护性作用干扰素生产。在这项 R03 试点研究中，我们将研究通过 RIG-I 识别细菌的假设促进保护性神经胶质反应。这些试点研究的结果将扩展我们对 RIG-I 功能和细菌攻击期间神经胶质细胞的调节，并开始评估新型合成物的体外保护作用核酸纳米颗粒RIG-I激动剂。总的来说，这些试点研究将为未来提供坚实的理论依据综合分析 RIG-I 介导的神经胶质反应在中枢神经系统细菌感染中的相对重要性，以及新型合成 RIG-I 激动剂治疗潜力的体内检查。