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.

项目摘要 细菌性脑膜炎是中枢神经系统（CNS）最常见的严重感染，主要感染 全世界的死亡和残疾原因，尤其是在儿童中。虽然抗生素疗法已经改变 细菌性脑膜炎从统一致命疾病到经常可治愈的疾病，总体结果仍然存在 不利，死亡率为5％至10％，永久性神经后遗症发生在5至40％的幸存者中， 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。但是，关于第一个的知之甚少 细菌病原体与启动此事件链的BBB之间的关键相互作用，可能 最终确定脑膜炎患者中较差或有利的神经系统结局。该提议试图 阐明细菌感染期间BBB破坏的分子机制，以及为什么它作为一个 细菌性脑膜炎期间的神经保护障碍。我们已经表明细菌感染诱导上皮 到内皮细胞中的间充质转变（EMT）程序（ENDOMT），破坏了BBB的紧密连接 内皮通过宿主转录因子Snail1的上调，这是一个紧密连接的全球阻遏物。 此外，我们发现细菌粘附蛋白直接与中间丝蛋白相互作用 在EMT/endomt期间诱导的蛋白质。我假设BBB破坏可能是由于合并 细菌进入和调节宿主信号通路的影响，从而导致屏障功能受损。 此外，与中枢神经系统疾病相关的细菌病原体具有渗透大脑的独特能力 内皮，最终导致BBB功能障碍。这些假设将在体外均可解决 使用B组链球菌（GBS）作为模型人类病原体的BBB穿透体体内模型 与脑膜炎有关。目标1：表征启动Snail1激活和 GBS脑膜炎期间Snail1对BBB分解的贡献；目标2：表征主机因素 在GBS感染期间有助于蜗牛1激活；目标3：确定GBS-Vimentin的贡献 与BBB渗透和脑膜炎发展的相互作用。这些研究应该增加我们的 了解与脑内皮相互作用所涉及的细菌和宿主因素，这导致 障碍破坏，病原体转移到大脑以及疾病进展。