Characterization of a novel murine model of central nervous system catheter infec

描述（由申请方提供）：脑脊液（CSF）分流管感染是儿科人群脑积水治疗中常见的严重并发症，报告的发生率为5 - 15%1。导致这些中枢神经系统（CNS）导管感染的最常见微生物，表皮葡萄球菌和金黄色葡萄球菌，均已知形成生物膜2，3。这些生物膜是聚集在导管表面上的有组织的细菌细胞群落，封闭在保护生物体的自生基质中。生物膜逃避宿主免疫应答和抗微生物剂的能力使得难以非手术地管理CNS导管感染，使得目前需要移除导管以有效地治疗这些感染。虽然微生物学家正在广泛研究生物膜形成所需的细菌的生长特性和其他适应性，但对宿主与生物膜的相互作用，特别是对导管生物膜感染的免疫反应知之甚少。为了探讨中枢神经系统导管感染的神经免疫反应，我开发了一种新的小鼠中枢神经系统导管感染模型。该技术导致了与S一致的导管相关感染。金黄色葡萄球菌和脑室炎，类似于人类脑室分流感染的后遗症。该模型的建立提供了一个强有力的工具，通过使用基因工程敲除或转基因小鼠品系来鉴定宿主对CNS生物膜的免疫应答中的重要因素。本研究的目的是利用这种CNS导管感染模型来表征宿主对CNS生物膜感染S.通过研究这种环境下细菌生长动力学和宿主先天免疫反应来研究金黄色葡萄球菌。了解神经免疫系统和受感染导管上形成的生物膜之间的相互作用将使我们能够在未来的研究中探索这些感染的新管理策略。该K08提案的总体假设是，大脑中的宿主先天性免疫应答响应于CNS导管的生物膜定殖而被主动减弱。为了验证这一假设，我们将进行两个特定目标的实验。在目标1中，我们将在CNS导管感染的小鼠模型中表征细菌生长动力学和先天性免疫应答。在目标2中，我们将通过使用一个同基因突变的S.金黄色葡萄球菌菌株，缺乏sarA表达，已知其在生物膜形成中起作用。最后，候选人是一名儿科感染性疾病专家，长期关注CNS感染和宿主反应在儿科感染中的作用。她是一个很好的支持候选人，成为一名医生科学家谁将从临床科学家发展奖受益匪浅的热切兴趣。

DESCRIPTION (provided by applicant): Cerebrospinal fluid (CSF) shunt infections are a frequent and serious complication in the treatment of hydrocephalus in the pediatric population, with a reported incidence of 5-15%1. The most common organisms responsible for these central nervous system (CNS) catheter infections, Staphylococcus epidermidis and Staphylococcus aureus, are both known to form biofilms2,3. These biofilms are organized communities of bacterial cells that aggregate on the catheter surface, enclosed in a self-produced matrix that protects the organisms. The biofilm's ability to evade the host immune response and antimicrobial agents makes it difficult to manage CNS catheter infections non-surgically, such that catheter removal is currently required to effectively treat these infections. While the growth characteristics and other adaptations of the bacteria required for biofilm formation are being extensively investigated by microbiologists, very little is known about the host interaction with the biofilm, particularly with regard to the immune response to catheter biofilm infections. To explore the neuroimmune response to CNS catheter infections, I have developed a novel model of CNS catheter infection in the mouse. This technique results in a consistent catheter-associated infection with S. aureus and ventriculitis, similar to the sequelae seen in humans with ventricular shunt infections. Establishment of this model provides a powerful tool to identify important factors in the host immune response to CNS biofilms through the use of genetically engineered knockout or transgenic mouse strains. The objective of this study is to utilize this model of CNS catheter infection to characterize the host immune response to a CNS biofilm infection with S. aureus by investigating the kinetics of bacterial growth and the host innate immune response in this setting. Understanding the interactions between the neuroimmune system and the biofilms that form on infected catheters will allow us to explore novel management strategies for these infections in future studies. The overall hypothesis of this K08 proposal is that the host innate immune response in the brain is actively attenuated in response to biofilm colonization of a CNS catheter. To test this hypothesis, we will perform experiments outlined in two specific aims. In Aim 1, we will characterize the bacterial growth kinetics and innate immune response in a murine model of CNS catheter infection. In Aim 2, we will define the role of bacterial regulatory factors in the development of CNS catheter infection by using an isogenic mutant S. aureus strain, deficient in sarA expression, which is known to play a role in biofilm formation. Finally, the candidate is a pediatric infectious disease specialist with a long-standing interest in CNS infections and the role of the host response in pediatric infections. She is a well-supported candidate with an avid interest in becoming a physician scientist who will benefit highly from a Clinical Scientist Development Award.