Blood-Brain Barrier Failure in Bacterial Meningitis

描述（由申请人提供）：细菌性脑膜炎是中枢神经系统（CNS）最常见的严重感染。即使得到适当治疗，仍有3-25%的患者可能死亡或出现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，血源性细菌必须与血脑屏障（BBS）相互作用并突破。细菌病原体对血脑屏障的渗透是多因素的，反映了宿主内皮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中枢神经系统通路，但对血脑屏障内皮对入侵病原体的初始威胁的特异性反应知之甚少。我认为血屏障不仅是一个物理屏障，而且积极参与宿主防御细菌病原体威胁的第一道防线。本研究旨在了解血脑屏障对细菌进入中枢神经系统的免疫功能，以及为什么在细菌性脑膜炎期间血脑屏障不能作为功能性屏障。我推测血脑屏障对细菌的反应是通过触发特定的先天免疫反应来招募中性粒细胞并防止中枢神经系统感染。我推测病原细菌进入脑内皮细胞的能力不成比例地激活或失调了这一反应途径，从而导致血脑屏障衰竭。最后，我假设血脑屏障的功能特别受到引起脑膜炎的细菌的阻碍。这些假设将在以下具体目标中得到解决：具体目标1：表征血脑屏障对中性粒细胞信号传导的先天免疫反应；具体目标2：评估细菌进入脑内皮对炎症失调和血脑屏障衰竭的贡献；特定目的3：研究血脑屏障是否以一种典型的物种特异性方式对不同细菌病原体的感染作出反应。

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.