Pathogenesis of bacterial meningitis

细菌性脑膜炎的发病机制

• 批准号: 9303283
• 负责人: Kwang S Kim
• 金额: $ 16.2万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9303283
• 关键词: Adherens Junction; Adult; Affect; Bacteria; Bacterial Meningitis; Biological; Blood - brain barrier anatomy; Brain; Cancer Patient; Cell Proliferation; Child; Collagen; Development; Developmental Disabilities; Disease; Endothelial Cells; Epidermal Growth Factor Receptor; Escherichia coli; Exhibits; Experimental Animal Model; Hematogenous; Human; Invaded; Knowledge; Meningitis; Modeling; Morbidity - disease rate; Neonatal; Neuraxis; Neurologic; Non-Small-Cell Lung Carcinoma; Pathogenesis; Penetration; Play; Pneumonia; Preclinical Drug Evaluation; Prevention therapy; Property; Protein Tyrosine Kinase; Proteins; Public Health; Resources; Role; Signal Transduction; Streptococcus Group B; Streptococcus pneumoniae; Surveillance Program; Survivors; Tight Junctions; base; brain endothelial cell; cancer therapy; carcinogenesis; cerebral microvasculature; innovation; interest; metropolitan; migration; monolayer; mortality; novel; novel strategies; postnatal; targeted treatment; tumor progression

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.

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， 导致这种死亡率和发病率的主要因素是我们对这种疾病的发病机制认识不全。 大肠埃希菌（E.大肠杆菌）和B族链球菌（GBS）是引起 新生儿脑膜炎，但致病性E。大肠杆菌和GBS脑膜炎仍然没有完全了解。 从人类病例和实验动物模型中获得的几条证据。大肠杆菌和GBS脑膜炎 表明E.大肠杆菌和GBS进入脑的渗透最初发生在脑微血管中。自E. 大肠杆菌和GBS渗透入脑发生在脑微血管，我们开发了血液- 利用人脑微血管内皮细胞（HBMEC）构建脑屏障模型，研究E.大肠杆菌和GBS 穿透血脑屏障。我们的HBMEC单层，在胶原包被的Transwell上培养后， 显示紧密连接和粘附连接蛋白的空间组织以及极化单层，这是一种独特的 血脑屏障内皮细胞的特性。脑膜炎分离株E.大肠杆菌和GBS已经被证明 显示出侵袭HBMEC单层的能力，并且显示出HBMEC侵袭的能力与 穿透大脑因此，我们使用E。大肠杆菌和GBS侵袭HBMEC单层作为一种新的免疫抑制剂。 生物学相关的方法，用于发现影响E.大肠杆菌和GBS对血液的渗透 脑屏障，脑膜炎发展的重要步骤。我们的方法的可行性是由我们的 鉴定影响E.大肠杆菌和GBS穿透 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（S.肺炎），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尚未被确认为 对E. coli、GBS和S.肺炎性脑膜炎阐明EGFR对E.大肠杆菌， GBS和S.因此，肺炎杆菌对血脑屏障的渗透将增强我们对肺炎杆菌感染的认识。 细菌性脑膜炎的发病机制。这种探索性应用的创新方面是调查一个 新的目标利用常见的脑膜炎引起的细菌（E。coli、GBS和S.肺炎）， 穿透血脑屏障。从这个应用程序中获得的信息将提供一个新的范例 探讨细菌性脑膜炎的发病机制及防治。