The Role of Complement in Cerebrospinal Fluid Shunt Infections

项目总结 脑脊液分流感染是脑积水治疗中常见而严重的并发症， 发生在5%-30%的患者1、2。这些感染与重要的长期神经疾病有关 后遗症，如智商降低，学习成绩差，癫痫发作的风险增加9-13。其作用机制 与分流感染相关的严重神经损伤的责任尚不清楚。 研究表明，补体通过发育在正常神经发育中的作用。 适当的补体通过小胶质细胞19、20、22介导突触修剪。更多的研究揭示了 补体在多种神经系统疾病和感染中的作用支持补体的中枢作用 在中枢神经系统内稳态和病理学方面24-33。分流动物模型的初步研究 感染后第5天，脑组织中补体C3和C5水平升高 当细菌负荷较低时为10，提示补体可能介导神经损伤 与分流感染有关。我的初步数据进一步支持了这一点 在C3基因敲除的小鼠中，修剪没有那么戏剧性。这项建议的总体目标是了解 补体在小鼠中枢神经系统导管感染模型中的应用，为今后鉴定新的 限制儿科患者神经损害的治疗目标。了解相关机制 补体介导神经损伤将使我们能够利用许多 正在为临床医学开发的补体抑制剂，作为潜在的佐剂 抗生素治疗以改善患者的长期结果35，36。 我们的中心假设是补体成分诱导小胶质细胞介导的突触修剪，并 对晚期脑水肿负有责任。为了验证这一假设，我们将执行两个概述的实验 明确的目标。在目标1中，我们将确定中枢神经系统S的补体途径激活的主要模式。 表皮导管相关性感染及其功能重要性。在目标2中，我们将定义分子 中枢神经系统导管感染时补体介导的损伤机制。 最后，应聘者是一名儿科传染病专家，具有长期的调查经验。 分流感染。她是一位备受支持的候选人，目标是成为一名内科科学家，她将 高度受益于临床科学家发展奖。

PROJECT SUMMARY Cerebrospinal fluid shunt infections are a frequent and serious complication of the treatment of hydrocephalus, occurring in 5-30% of patients1, 2. These infections are associated with significant long-term neurologic sequelae such as lower IQ, poor school performance and increased risk of seizures 9-13. The mechanisms responsible for the severe neurologic damage associated with shunt infection are unknown. Studies have demonstrated the role of complement in normal neurologic development through developmentally appropriate complement mediated synaptic pruning by microglia 19,20,22. Additional studies have revealed the role of complement in a variety of neurologic disorders and infection supporting a central role for complement in central nervous system homeostasis and pathology24-33. My preliminary studies in an animal model of shunt infection have demonstrated elevated levels of the complement components C3 and C5 in brain tissue at day 5 and 10 when bacterial burdens are low, suggesting complement may mediate the neurologic damage associated with shunt infections. This is further supported by my preliminary data demonstrating that synaptic pruning is less dramatic in C3 knockout mice. The overall objective of this proposal is to understand the role of complement in a murine model of CNS catheter infection, to facilitate the future identification of novel therapeutic targets to limit neurologic damage in pediatric patients. Understanding the mechanisms whereby complement mediates neurologic damage would allow us to take advantage of many complement inhibitors that are being developed for clinical medicine as potential adjuvants to antibiotic therapy to improve long-term patient outcomes 35,36. Our central hypothesis is that complement components induce microglial-mediated synaptic pruning and are responsible for late-stage cerebral edema. To test this hypothesis, we will perform experiments outlined in two specific aims. In Aim 1, we will identify the primary mode of complement pathway activation during CNS S. epidermidis catheter-associated infection and functional importance. In Aim 2, we will define the molecular mechanisms of complement-mediated damage during CNS catheter infection. Finally, the candidate is a pediatric infectious disease specialist with a long-standing experience investigating shunt infections. She is a well-supported candidate with the goal of becoming a physician scientist and would highly benefit from a Clinical Scientist Development Award.