Project 3

项目摘要 莱姆病是美国最流行的节肢动物传播疾病，据报道有3万多例 2010年提交给疾病控制与预防中心。该病的病原体是疏螺旋体 伯氏螺旋体（Bb），并通过受感染的蜱叮咬传播给人类。治疗期间使用抗生素 疾病的初始阶段是有效的，尽管大约25%的患者接受抗生素治疗， 患有关节炎和其他莱姆病后综合征; 2在那些接受神经疏螺旋体病治疗的患者中， 许多人经历了包括记忆障碍和认知变化在内的挥之不去的症状。最近我们 实验室已经证明，1）Bb可以在感染大鼠的大脑中检测到; 2）Bb可以引起 大脑中的神经炎性变化重现了人类患者和非人灵长类动物中观察到的变化 模型;和3）杀死的Bb可以诱导大脑中的炎症反应，表明死亡 抗生素治疗后残留的微生物和螺旋体碎片可导致神经病理学。 我们的中心假设是莱姆病神经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 神经性疏螺旋体病的持续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测试这一假设与3个特定的目标。在 具体目标1，我们将描述Bb诱导的炎症的程度和Bb诱导的炎症的持续性。 螺旋体的碎片。在第二个具体目标中，我们将量化神经元凋亡， 认知缺陷由杀虫剂杀死的Bb引起。最后，在具体目标3中，我们将确定 介导BB诱导的神经炎症和细胞凋亡的途径。我们的研究结果将有助于 为制定预防和潜在干预战略提供必要的知识基础 莱姆病后神经系统综合征的治疗。

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.