Blood-Brain Barrier Failure in Bacterial Meningitis

描述（由申请方提供）：细菌性脑膜炎是中枢神经系统（CNS）最常见的严重感染。即使有适当的治疗，3-25%的受影响个体可能死亡或遭受永久性神经系统后遗症，包括脑梗死，脑瘫，认知缺陷，失明，耳聋或癫痫发作。为了产生脑膜炎，血液传播的细菌必须与血脑屏障（BBS）相互作用并突破血脑屏障。细菌病原体穿透血脑屏障是多因素的，反映了宿主内皮细胞和微生物产物之间复杂的相互作用。虽然细菌性脑膜炎的实验模型已经阐明了脑炎症和神经元损伤的CNS途径，但关于BBB内皮对入侵病原体的初始威胁的特异性反应知之甚少。我认为血脑屏障不仅仅是一个物理屏障，而是积极参与宿主防御细菌病原体威胁的第一道防线。该提案旨在了解BBB对细菌CNS进入的免疫功能，以及为什么BBB在细菌性脑膜炎期间不能作为功能屏障。我推测血脑屏障对细菌的反应是通过引发特异性的先天免疫反应来募集中性粒细胞并防止CNS感染。我假设致病菌进入脑内皮细胞的能力不成比例地激活或失调这一反应途径，从而导致BBB衰竭。最后，我假设血脑屏障的功能是由脑膜炎引起的细菌特别阻碍。这些假设将在以下具体目标中得到解决：具体目标1：表征BBB对中性粒细胞信号传导的先天免疫应答;具体目标2：评估细菌进入脑内皮对炎症性失调和BBB衰竭的贡献;具体目标3：研究BBB是否以典型的物种特异性方式对不同细菌病原体的感染作出应答。

DESCRIPTION (provided by applicant): Bacterial meningitis is the most common serious infection of the central nervous system (CNS). Even with proper treatment, 3-25% of affected individuals may die or suffer permanent neurological sequelae including cerebral infarction, cerebral palsy, cognitive deficits, blindness, deafness or seizures. In order to produce meningitis, blood-borne bacteria must interact with and breech the blood-brain barrier (BBS). Penetration of the BBB by a bacterial pathogen is multifactorial and reflects a complex interplay between the host endothelium and microbial products. While experimental models of bacterial meningitis have clarified CNS pathways of brain inflammation and neuronal injury, much less is known about the specific response of BBB endothelium to the initial threat of an invading pathogen. I propose that the BBB is not merely a physical barrier but actively participates in the first line of host defense against the threat of bacterial pathogens. This proposal seeks to understand the immune function of the BBB against bacterial CNS entry, and why the BBB fails as a functional barrier during bacterial meningitis. I hypothesize that the BBB responds to bacteria by triggering a specific innate immune response to recruit neutrophils and prevent CNS infection. I postulate that the ability of pathogenic bacteria to enter inside brain endothelial cells disproportionately activates or dysregulates this response pathway, thereby contributing to BBB failure. Finally, I hypothesize that BBB function is thwarted specifically by meningitis causing bacteria. These hypotheses will be addressed in the following specific aims: Specific Aim 1: Characterize the innate immune response of the BBB for neutrophil signaling; Specific Aim 2: Assess the contribution of bacterial entry into brain endothelium to inflammatory dysregulation and BBB failure; Specific Aim 3: Investigate whether the BBB responds in a stereotypical of species-specific fashion to infection with different bacterial pathogens.