Project 3

项目总结 莱姆病是美国最常见的节肢动物传播疾病，据报道有30,000多例 2010年向疾病控制和预防中心捐款。这种疾病的病原体是疏螺旋体。 伯格多费氏病(BB)，通过受感染的扁虱叮咬传播给人类。术中使用抗生素治疗 疾病的初始阶段是有效的，尽管大约25%的接受抗生素治疗的患者继续 患有关节炎和其他莱姆病后综合征；在接受神经疏螺旋体病治疗的患者中， 许多人会有挥之不去的症状，包括记忆障碍和认知变化。最近，我们的 实验室已经证明，1)在感染的大鼠的大脑中可以检测到BB；2)BB可以引起 脑内神经炎性改变概括了人类患者和非人类灵长类动物的变化 模型；3)抗生素灭活的BB可以在大脑中引发炎症反应，这表明死亡的 抗生素治疗后残留的微生物和螺旋体碎片可能会导致神经病理。 我们的中心假设是，莱姆氏脑疏螺旋体病是由持续的BB诱导的 在没有活微生物的情况下的神经炎症反应。我们认为炎症 神经疏螺旋体病的挥之不去的症状是由于抗生素后细菌碎片的持续存在 治疗。 我们已经生成了几种试剂和方法来验证这一假设，并有三个特定的目标。在……里面 具体目标1我们将表征抗生素灭活的BB诱导的炎症和持久性的程度 大鼠大脑中的螺旋体碎片。在第二个具体目标中，我们将量化神经元凋亡和 抗生素致死的BB引起的认知缺陷。最后，在具体目标3中，我们将确定信令 介导BB诱导的神经炎症和细胞凋亡的途径。我们的发现将有助于 制定预防和潜在干预战略所需的知识库 莱姆病后神经综合征的治疗。

PROJECT SUMMARY Lyme disease is the most prevalent arthropod-borne disease in the US with more that 30,000 cases reported to the Centers for Disease Control and Prevention in 2010. The causative agent of the disease is Borrelia burgdorferi (Bb) and is transmitted to humans by the bite of infected ticks. Treatment with antibiotics during the initial stage of the disease is effective, although about 25% of the patients treated with antibiotics continue to suffer from arthritis and other post- Lyme disease syndromes; of those patients treated for neuroborreliosis, many experience lingering symptoms including memory impairment and changes in cognition. Recently, our laboratory has demonstrated that 1) Bb can be detected in the brains of infected rats; 2) Bb can cause neuroinflammatory changes in the brain that recapitulate those seen in human patients and nonhuman primate models; and 3) antibiotic-killed Bb can induce an inflammatory response in the brain, suggesting that dead microorganisms and spirochetal debris that remain after antibiotic treatment can contribute to neural pathology. Our central hypothesis is that Lyme neuroborreliosis results from a sustained Bb-induced neuroinflammatory response in the absence of live microorganisms. We believe that the inflammation and lingering symptoms of neuroborreliosis are due to the persistence of bacterial debris following antibiotic treatment. We have generated several reagents and methodologies to test this hypothesis with 3 Specific Aims. In Specific Aim 1 we will characterize the extent of antibiotic-killed Bb-induced inflammation and persistence of spirochetal debris in the brains of rats. In the second Specific Aim we will quantify neuronal apoptosis and cognitive deficits caused by antibiotic-killed Bb. Finally, in Specific Aim 3 we will determine the signaling pathways mediating Bb-induced neuroinflammation and apoptosis. Our findings will contribute to the knowledge base necessary for the development of intervention strategies for prevention and potentially treatment of post-Lyme disease neurological syndromes.