Modulation of Blood-Brain Barrier Defense and Dysfunction during Bacterial Meningitis

细菌性脑膜炎期间血脑屏障防御和功能障碍的调节

• 批准号: 10091536
• 负责人: Kelly S Doran
• 金额: $ 42.69万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10091536
• 关键词: Address; Adult; Age; Animal Model; Antibiotic Therapy; Bacterial Adhesins; Bacterial Infections; Bacterial Meningitis; Biochemical; Biological Models; Blocking Antibodies; Blood; Blood - brain barrier anatomy; Brain; Brain Edema; Cause of Death; Cell Adhesion; Cell Line; Cell Surface Receptors; Central Nervous System Diseases; Central Nervous System Infections; Ceramides; Child; Clinical; Cytoskeleton; Data; Development; Disease; Disease Progression; Endothelial Cells; Endothelium; Epidermal Growth Factor Receptor; Event; Failure; Functional disorder; Human; Immune signaling; In Vitro; Infection; Integration Host Factors; Intermediate Filament Proteins; Intracranial Hypertension; Invaded; Knockout Mice; Life; Lipids; MAP Kinase Gene; Mediating; Membrane Microdomains; Meningitis; Mitogen-Activated Protein Kinases; Molecular; Natural Immunity; Neoplasm Metastasis; Neuraxis; Neurologic; Neurological outcome; Newborn Infant; Nutrient; Outcome; Pathogenesis; Pathway interactions; Patients; Process; Publishing; Receptor Inhibition; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Research Proposals; Role; Seizures; Signal Pathway; Signal Transduction; Snails; Streptococcal Infections; Streptococcus Group B; Streptococcus adhesin; Structure; Survivors; Tight Junctions; Tissues; Transcription Repressor; Up-Regulation; Venous; Vimentin; Work; Zinc Fingers; blood-brain barrier disruption; blood-brain barrier penetration; blood-brain barrier permeabilization; brain endothelial cell; cerebrovascular; disability; epithelial to mesenchymal transition; human model; human pathogen; in vivo; in vivo Model; inhibitor/antagonist; knock-down; mortality; novel; overexpression; pathogen; pathogenic bacteria; programs; transcription factor

PROJECT SUMMARY Bacterial meningitis is the most common serious infection of the central nervous system (CNS) and a major cause of death and disability worldwide, especially in children. Although antibiotic therapy has changed bacterial meningitis from a uniformly fatal disease to an often curable one, the overall outcome remains unfavorable, with mortality of 5 to 10% and permanent neurologic sequelae occurring in 5 to 40% of survivors, depending on patient age and pathogen. Disruption and dysfunction of the blood-brain barrier (BBB) is a hallmark event in the pathophysiology of bacterial meningitis. Little is known, however, about the very first and crucial interaction between a bacterial pathogen with the BBB that initiates this chain of events, and may ultimately determine a poor or favorable neurological outcome in meningitis patients. This proposal seeks to elucidate the molecular mechanisms of BBB disruption during bacterial infection, and why it fails as a neuroprotective barrier during bacterial meningitis. We have shown that bacterial infection induces an epithelial to mesenchymal transition (EMT) program in endothelial cells (EndoMT), disrupting tight junctions in BBB endothelium through the upregulation of host transcription factor Snail1, a global repressor of tight junctions. Further, we have discovered that a bacterial adhesin interacts directly with vimentin, an intermediate filament protein that is induced during EMT/EndoMT. I hypothesize that BBB disruption may be due to the combined effect of bacterial entry and modulation of host signaling pathways that results in compromised barrier function. Further that bacterial pathogens associated with CNS disease possess the unique ability to penetrate brain endothelium, which ultimately leads to BBB dysfunction. These hypotheses will be addressed with both in vitro and in vivo models of BBB penetration using Group B streptococcus (GBS) as a model human pathogen associated with meningitis. AIM 1: Characterize the bacterial determinant(s) that initiate Snail1 activation and the contribution of Snail1 to BBB breakdown during GBS meningitis; AIM 2: Characterize the host factors that contribute to Snail1 activation during GBS infection; AIM 3: Determine the contribution of GBS-vimentin interaction to BBB penetration and the development of meningitis. These studies should increase our understanding of the bacterial and host factors involved in the interaction with brain endothelium that leads to barrier disruption, pathogen transit into the brain, and disease progression.

项目总结 细菌性脑膜炎是最常见的严重中枢神经系统感染，也是一种主要的 世界范围内的死亡和残疾原因，特别是儿童。尽管抗生素疗法已经改变了 细菌性脑膜炎从一种普遍致命的疾病转变为一种通常可以治愈的疾病，总体结果仍然是 不利的是，死亡率为5%至10%，5%至40%的幸存者出现永久性神经后遗症， 取决于患者的年龄和病原体。血脑屏障(BBB)的破坏和功能障碍是 细菌性脑膜炎病理生理学的标志性事件。然而，人们对第一个和第二个 细菌病原体与启动这一连串事件的血脑屏障之间的关键相互作用，并可能 最终确定脑膜炎患者的神经预后差或好。这项建议旨在 阐明细菌感染时血脑屏障破坏的分子机制，以及为什么它作为一种 细菌性脑膜炎时的神经保护屏障。我们已经证明，细菌感染会诱导上皮样病变 内皮细胞间充质转化(EMT)程序(EndoMT)，破坏血脑屏障紧密连接 通过宿主转录因子Snail1上调内皮细胞，Snail1是紧密连接的全球抑制因子。 此外，我们还发现细菌粘附素直接与中间纤维波形蛋白相互作用。 在EMT/EndoMT过程中诱导的蛋白质。我推测血脑屏障的中断可能是由于 细菌进入和调节宿主信号通路导致屏障功能受损的影响。 此外，与中枢神经系统疾病相关的细菌病原体具有独特的穿透大脑的能力 内皮，最终导致血脑屏障功能障碍。这些假说将在体外实验中得到解决 以B组链球菌(GBS)为模型人类病原体的血脑屏障穿透体内模型 与脑膜炎有关。目的1：鉴定启动Snail1激活和激活的细菌决定簇(S) Snail1在GBS脑膜炎时血脑屏障破坏中的作用；目的2：表征宿主因素 在GBS感染过程中参与Snail1的激活；目的3：确定GBS-vientin的作用 血脑屏障穿透与脑膜炎发生的相互作用。这些研究应该会增加我们的 了解与脑内皮细胞相互作用所涉及的细菌和宿主因素 屏障破坏、病原体进入大脑和疾病进展。