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

项目摘要 细菌性脑膜炎和脑膜脑炎是导致永久性残疾的严重临床症状，可 甚至在数小时内造成死亡。现在人们认识到，驻留的胶质细胞，如小胶质细胞和星形胶质细胞，在 在保护性和有害免疫反应中发挥重要作用，以及这种对细菌感染的反应 中枢神经系统(CNS)是通过依赖于模式识别受体(PRR)的病原体识别而启动的 图案。因此，确定神经胶质细胞细菌识别的机制有可能识别新的 治疗靶点。我们和其他人已经证明，神经胶质细胞使用细胞表面和胞质PRR的组合来 确定病原体的模体。有趣的是，虽然维甲酸诱导基因-I(RIG-I)是已知的识别病毒核酸的基因 酸，最近的证据表明，胞质中的PRR可能在细菌核鉴定中发挥新的作用 酸。与表面PRRs可能引发的潜在破坏性炎症反应不同，RIG-I 激活刺激干扰素的产生，从而形成对感染的保护性、先天和适应性免疫反应。 到目前为止，rig-i识别胶质细胞中的细菌核酸从而促进抗菌反应的能力已经 没有被探索过。我们最近公布的数据表明，暴露后小胶质细胞中RIG-I的表达上调 与中枢神经系统临床相关的不同细菌病原体有关，这种挑战可以启动潜在的保护性 干扰素的生产。在这项R03先导研究中，我们将调查通过RIG-I识别细菌的假设 促进保护性神经胶质反应。这些先导研究的结果将扩大我们对RIG-I功能和 细菌攻击过程中神经胶质细胞的调节，并开始评价一种新的合成化合物的体外保护作用 核酸纳米颗粒RIG-I激动剂。总体而言，这些初步研究将为未来提供坚实的理由 综合分析RIG-I介导的神经胶质反应在细菌感染中枢神经系统中的相对重要性， 以及对新型合成Rig-I激动剂的治疗潜力的体内检查。

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.