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疾病， 甚至在几小时内造成死亡现在认识到，常驻神经胶质细胞，如小胶质细胞和星形胶质细胞，在神经胶质细胞中起作用。 在保护性和有害的免疫应答中起重要作用，并且这种对细菌感染的应答 中枢神经系统（CNS）是通过模式识别受体（PRR）依赖性病原体识别启动的 图案因此，确定神经胶质细菌识别的潜在机制有可能识别新的神经胶质细胞。 治疗目标我们和其他人已经表明，神经胶质细胞使用细胞表面和胞质PRR的组合， 鉴定病原体基序。有趣的是，虽然维甲酸诱导基因-I（RIG-I）已知识别病毒核酸， 最近的证据表明，这种胞质PRR可能在鉴定细菌核酸中发挥新的作用， acids.与表面PRR可能引发的潜在破坏性炎症反应相反，RIG-I 激活刺激干扰素产生，形成对感染的保护性先天和适应性免疫应答。 迄今为止，RIG-I鉴定神经胶质细胞中细菌核酸从而促进抗菌反应的能力已经被证实。 尚未被探索。我们最近发表的数据表明，RIG-I表达上调小胶质细胞暴露后， 不同的临床相关细菌病原体的CNS，这样的挑战可以启动潜在的保护性 干扰素生产。在这项试验性R 03研究中，我们将研究通过RIG-I的细菌识别 促进保护性神经胶质反应。这些初步研究的结果将扩大我们对RIG-I功能的了解， 调节神经胶质细胞在细菌的挑战，并开始，以评估在体外保护作用的一种新的合成 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的 RIG-I介导的神经胶质反应在CNS细菌感染中的相对重要性的综合分析， 以及新的合成RIG-1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.