Pathogenesis of bacterial meningitis

细菌性脑膜炎的发病机制(一种新的R21) 摘要 细菌性脑膜炎仍然是死亡和发病的一个重要原因，也是一个主要因素。 导致这种死亡率和发病率的因素是我们对这种疾病的发病机制的不完全了解。 大肠埃希氏菌和B群链球菌是两种最常见的致病菌 新生儿脑膜炎，但大肠杆菌和GBS脑膜炎的发病机制仍不完全清楚。 来自人类病例和实验性动物模型的大肠杆菌和GBS脑膜炎的几条证据 表明大肠杆菌和GBS最初在脑微血管中渗透到大脑中。由于E. Coli和GBS在脑微血管中渗透到大脑中，我们开发了血液- 利用人脑微血管内皮细胞建立脑屏障模型研究大肠杆菌和GBS 穿透血脑屏障。我们的HBMEC单层，通过培养在胶原蛋白涂层的Trswells上， 展示了紧密和粘连连接蛋白的空间组织以及极化的单分子层，这是一种独特的 血脑屏障内皮细胞的特性。脑膜炎分离的大肠杆菌和GBS已被证明 表现出侵袭HBMEC单层的能力与HBMEC侵袭能力呈正相关 通过渗透到大脑中。因此，我们使用大肠杆菌和GBS对HBMEC单层的侵袭作为 发现影响大肠杆菌和GBS对血液渗透的新靶点的生物学相关方法- 脑屏障，脑膜炎发展过程中的关键步骤。我们的方法的可行性通过我们的 影响大肠杆菌和GBS穿透的表皮生长因子受体酪氨酸激酶的鉴定 血脑屏障。与细菌性脑膜炎特别相关的是我们的初步证明 肺炎链球菌(肺炎链球菌)，儿童和成人细菌性脑膜炎的主要原因， 还利用EGFR穿透血脑屏障。EGFR尚未得到认可，因为它 对大肠杆菌、格林-巴利综合征和肺炎链球菌脑膜炎的贡献。阐明EGFR在大肠杆菌中的作用， 因此，GBS和肺炎链球菌对血脑屏障的穿透将增强我们对 细菌性脑膜炎的发病机制。此探索性应用程序的创新方面是研究一个 常见脑膜炎致病细菌(大肠杆菌、GBS和肺炎链球菌)开发的新靶点 穿透血脑屏障。从该应用程序派生的信息将提供一种新的范例 目的：探讨细菌性脑膜炎的发病机制及防治。

Pathogenesis of bacterial meningitis (a new R21) Abstract Bacterial meningitis continues to be an important cause of mortality and morbidity, and a major contributing factor to such mortality and morbidity is our incomplete knowledge on the pathogenesis of this disease. Escherichia coli (E. coli) and group B Streptococcus (GBS) are the two most common bacteria causing neonatal meningitis, but the pathogenesis of E. coli and GBS meningitis remains incompletely understood. Several lines of evidence from human cases and experimental animal models of E. coli and GBS meningitis indicate that E. coli and GBS penetration into the brain occurs initially in the cerebral microvessels. Since E. coli and GBS penetration into the brain occurred in the cerebral microvasculature, we developed the blood- brain barrier model with human brain microvascular endothelial cells (HBMEC) to investigate E. coli and GBS penetration of the blood-brain barrier. Our HBMEC monolayer, upon cultivation on collagen-coated Transwells, exhibits spatial organization of tight and adherens junction proteins as well as a polarized monolayer, a unique property of the blood-brain barrier endothelial cells. Meningitis isolates of E. coli and GBS have been shown to exhibit the ability to invade the HBMEC monolayer and the ability of HBMEC invasion is shown to be correlated with penetration into the brain. We, therefore, used E. coli and GBS invasion of HBMEC monolayer as a biologically relevant approach for discovery of novel targets affecting E. coli and GBS penetration of the blood- brain barrier, the essential step in the development of meningitis. A feasibility of our approach is shown by our identification of epidermal growth factor receptor (EGFR) tyrosine kinase affecting E. coli and GBS penetration of the blood-brain barrier. Of particular relevance to bacterial meningitis is our preliminary demonstration that Streptoccous pneumoniae (S. pneumoniae), the leading cause of bacterial meningitis in children and adults, also exploits EGFR for penetration of the blood-brain barrier. EGFR has not been recognized for its contribution to E. coli, GBS and S. pneumoniae meningitis. Elucidation of EGFR for its contribution to E. coli, GBS and S. pneumoniae penetration of the blood-brain barrier will, therefore, enhance our knowledge on the pathogenesis of bacterial meningitis. The innovative aspect of this exploratory application is to investigate a new target exploited by common meningitis-causing bacteria (E. coli, GBS and S. pneumoniae) for their penetration of the blood-brain barrier. The information derived from this application will provide a new paradigm for investigating the pathogenesis, prevention and therapy of bacterial meningitis.