MicroRNAs induced in response to Borrelia burgdorferi

项目总结 莱姆病是美国最常见的节肢动物传播疾病。这种疾病的病原体是 伯氏疏螺旋体(BB)细菌，影响包括中枢神经系统在内的多个组织 (CNS)。挥之不去的症状包括疼痛、疲劳以及记忆和认知方面的困难，持续到 所有接受抗生素治疗的患者中有20%。治疗后莱姆病综合征的原因 (PTLDS)尚不清楚，也存在争议。 我们认为，活细菌不是推动中枢神经系统持续炎症所必需的。使用老鼠 在建立神经疏螺螺旋体病模型的基础上，我们证明了在没有活细菌的情况下，中枢神经系统炎症持续存在。 是什么导致了持续的炎症？我们还发现，BB可以诱导microRNA表达的变化 星形胶质细胞的变化包括miR-122-5p、miR-135a-3p、miR-135a-5p、miR-143-3p和miR-146b-5p。 这些microRNAs的靶标包括与细胞黏附、紧密连接、细胞信号和 对感染的反应。星形胶质细胞是应对损伤、神经元支持和组织修复的关键角色。 我们的工作假设是，神经症状是由BB诱导的microRNAs持续存在的 导致持续的神经炎性反应。 我们将用两个具体的目标来检验这一假设。在特定的目标1中，我们将开发一份完整的胶质细胞图谱- 与未感染脑组织相比，特定的microRNAs及其靶点可诱导脑脊液感染脑组织。在第二个 具体地说，我们将在原代胶质细胞中操纵microRNA介导的炎症介质 利用特定的microRNA抗原体，展示了改变的microRNA之间的机制联系 表达和炎症。 我们的长期目标是通过操纵microRNA在体内调节宿主中枢神经系统对BB的反应 表情。通过阐明导致神经炎症的特定microRNAs，我们将提供新的 莱姆病治疗的靶点。MicroRNA的模拟物和拮抗剂已经在人体试验中， 展示了这种疗法的潜在可行性。

PROJECT SUMMARY Lyme disease is the most prevalent arthropod-borne disease in the US. The causative agent of the disease is the bacterium Borrelia burgdorferi (Bb), which affects multiple tissues including the central nervous system (CNS). Lingering symptoms including pain, fatigue, and difficulties with memory and cognition persist in up to 20% of all patients treated with antibiotics. The cause of this Post-Treatment Lyme Disease Syndrome (PTLDS) is unclear and controversial. We propose that live bacteria are not required to drive persistent inflammation in the CNS. Using a rat model of neuroborreliosis, we demonstrated that CNS inflammation persists in the absence of live bacteria. What drives the persistent inflammation? We also found Bb can induce changes in microRNA expression changes in astrocytes including miR-122-5p, miR-135a-3p, miR-135a-5p, miR-143-3p and miR-146b-5p. Targets of these microRNAs include genes involved in cell adhesion, tight junctions, cell signaling, and response to infection. Astrocytes are key players in response to injury, neuronal support, and tissue repair. Our working hypothesis is that neurological symptoms are perpetuated by Bb-induced microRNAs that lead to a persistent neuroinflammatory response. We will test this hypothesis with 2 Specific Aims. In Specific Aim 1 we will develop a complete atlas of the glial- specific microRNAs and their targets induced Bb-infected brain relative to uninfected brain. In the second Specific Aim, we will manipulate microRNA-mediated inflammatory mediators in primary glial cells through the use of specific microRNA antagomirs, demonstrating the mechanistic link between altered microRNA expression and inflammation. Our long-term objective is to modulate host CNS responses to Bb in vivo through manipulation of microRNA expression. By elucidating the specific microRNAs that contribute to neuroinflammation, we will provide novel targets for Lyme disease therapy. MicroRNA mimics and antagonists are already in human trials, demonstrating the potential feasibility of such therapies.