Blood-Brain Barrier Failure in Bacterial Meningitis

描述(申请人提供)：细菌性脑膜炎是最常见的中枢神经系统(CNS)严重感染。即使得到适当的治疗，3%-25%的受影响个人也可能死亡或遭受永久性神经后遗症，包括脑梗塞、脑瘫、认知障碍、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)相互作用并形成屏障。细菌对血脑屏障的穿透是多因素的，反映了宿主内皮细胞和微生物产物之间的复杂相互作用。虽然细菌性脑膜炎的实验模型已经阐明了脑部炎症和神经元损伤的中枢神经系统通路，但对血脑屏障内皮细胞对入侵病原体最初威胁的特定反应知之甚少。我认为，血脑屏障不仅是一种物理屏障，而且积极参与宿主抵御细菌病原体威胁的第一道防线。这项建议试图了解血脑屏障对细菌中枢神经系统进入的免疫功能，以及为什么血脑屏障在细菌性脑膜炎中作为功能屏障失败。我推测，血脑屏障对细菌的反应是通过触发一种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，我假设血脑屏障功能受到细菌引起的脑膜炎的影响。这些假说将在以下特定目标中得到解决：特定目标1：表征血脑屏障对中性粒细胞信号的先天免疫反应；特定目标2：评估细菌进入脑内皮细胞对炎症调节失调和血脑屏障衰竭的贡献；特定目标3：研究血脑屏障是否以物种特有的方式对不同细菌病原体的感染做出反应。

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.