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E. coli penetration of the blood-brain barrier

大肠杆菌穿透血脑屏障

基本信息

批准号：
9243956
负责人：
Kwang S Kim
金额：
$ 20.25万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-15 至 2020-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9243956
关键词：
Adherens Junction Affect Allergic Reaction Bacteremia Bacterial Meningitis Binding Blood Blood - brain barrier anatomy Brain Cell Proliferation Collagen Developmental Delay Disorders Disease Endothelial Cells Escherichia coli Escherichia coli Meningitis Exhibits Experimental Animal Model Generations Human Impaired cognition In Vitro Infection Invaded Knowledge Lipids Meningitis Modeling Morbidity - disease rate Neurologic Organism Pathogenesis Penetration Prevention therapy Property Proteins PubMed Public Health Role SPHK1 enzyme Signal Transduction Sphingosine-1-Phosphate Receptor Survivors Tight Junctions Time angiogenesis base brain endothelial cell cerebral capillary cerebral microvasculature extracellular hearing impairment immunoreaction in vivo inhibitor/antagonist interest microorganism monolayer mortality novel novel strategies pathogen public health relevance sphingosine 1-phosphate sphingosine kinase

项目摘要

DESCRIPTION (provided by applicant): Bacterial meningitis continues to be an important cause of mortality and morbidity. A major contributing factor to such mortality and morbidity is our incomplete knowledge on the pathogenesis of this disease. E. coli is the most common Gram-negative bacillary organism causing meningitis, but the pathogenesis of E. coli meningitis remains incompletely understood. Several lines of evidence from human cases and experimental animal models of E. coli meningitis indicate that E. coli penetration into the brain follows a high level of bacteremia and cerebral capillaries are the portal of entry into the brain. Since E. coli penetration into the brain occurred in the cerebral microvasculature, we developed the blood-brain barrier model with human brain microvascular endothelial cells (HBMEC) to study E. coli 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. We have shown for the first time that meningitis-causing E. coli strains exhibit the ability to invade the HBMEC monolayer in vitro and that the ability of HBMEC invasion is correlated with E. coli penetration into the brain in vivo. The mechanisms involved in E. coli penetration of the blood-brain barrier, however, remain incompletely understood. Our preliminary studies revealed a novel mechanism exploited by meningitis-causing E. coli for invasion of the blood-brain barrier, and also suggest that such mechanism is likely to contribute to another meningitis-causing pathogen for penetration of the blood-brain barrier. Determination and characterization of such new mechanism will, therefore, provide a paradigm-shifting strategy for elucidating the pathogenesis of bacterial meningitis.

描述(申请人提供)：细菌性脑膜炎仍然是死亡和发病的重要原因。造成这种死亡率和发病率的一个主要因素是我们对这种疾病的发病机制了解不够全面。大肠埃希菌是引起脑膜炎的最常见的革兰氏阴性杆菌，但其发病机制仍不完全清楚。来自人类病例和实验动物模型的几条证据表明，大肠杆菌进入大脑之前有高水平的菌血症，而大脑毛细血管是进入大脑的门户。由于大肠杆菌穿透脑微血管是发生在脑微血管内，我们利用人脑微血管内皮细胞(HBMEC)建立了血脑屏障模型，以研究大肠杆菌对血脑屏障的穿透。我们的HBMEC单层在胶原包裹的Trswells上培养后，显示出紧密和粘连连接蛋白的空间组织以及极化的单层，这是血脑屏障内皮细胞的独特属性。我们首次证明了引起脑膜炎的大肠杆菌在体外表现出入侵HBMEC单层的能力，并且HBMEC的入侵能力与大肠杆菌在体内的脑渗透有关。然而，有关大肠杆菌穿透血脑屏障的机制仍不完全清楚。我们的初步研究揭示了引起脑膜炎的大肠杆菌入侵血脑屏障的一种新机制，并表明这种机制可能有助于另一种导致脑膜炎的病原体穿透血脑屏障。因此，这种新机制的确定和表征将为阐明细菌性脑膜炎的发病机制提供一种范式转换策略。