Leukocyte Transmigration in Neonatal Candida Meningitis

新生儿念珠菌脑膜炎中的白细胞迁移

• 批准号: 6669927
• 负责人: ALBERT S LOSSINSKY
• 金额: $ 7.46万
• 依托单位: HUNTINGTON MEDICAL RESEARCH INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6669927
• 关键词: Candida albicans; blood brain barrier; candidiasis; cell adhesion; cell migration; chemoattractants; disease /disorder onset; high voltage electron microscopy; histology; immunocytochemistry; inflammation; laboratory rat; leukocyte adhesion molecules; leukocytes; meninges; meningitis; newborn animals; scanning electron microscopy; transmission electron microscopy

DESCRIPTION (provided by applicant): Neonatal meningitis produced by opportunistic pathogenic microorganisms such as the yeast Candida albicans is an inflammatory condition that can occur during the first month after birth and is a leading cause of neurodegenerative states and morbidity in premature and immunocompromised infants. Meningitis in neonates is attributable to the incomplete development of the CNS, the blood-brain barrier (BBB) and the immune system. The precise nature of adhesion and transmigration of pathogenic organisms and leukocytes across the BBB during inflammatory conditions remains unclear and is an issue of great interest in modern medicine. This research program will focus at the mechanisms of adhesion and transmigration of C. albicans and inflammatory leukocytes that appear in response to the microorganisms during the process of meningitis. Our study will be conducted in an in vivo model of experimentally induced meningitis in neonatal rats. Our hypothesis states that the pathogenic yeast C. albicans initially induce the inflammatory state in the meningeal blood vessels. Subsequently, leukocytes adhere to and traverse the endothelial cell (EC) barrier stimulated by the local release of chemoattractant substances in response to the yeast cells. The entire process of adhesion and transmigration across the BBB is facilitated by adhesion molecules including ICAM-1, PECAM-1 and VCAM-1 either across the ECs by a transcellular pathway, through EC junctional complexes by a paracellular pathway, or by both mechanisms. Our specific aim of the project will be to define and compare the light microscopic, immunohistochemical, ultrastructural and immunoultrastructural nature of adhesion and transmigration of a virulent strain of C. albicans, and the different major subsets of inflammatory leukocytes including neutrophils, mononuclear cells and lymphocytes that appear in response to the yeast-induced meningoencephalitis in neonatal rats. This will lay the groundwork for us to investigate how adhesion molecules regulate the attachment and transmigration of pathogenic yeast cells and leukocytes across the BBB via specialized anatomical "gateways to the brain" through either modified EC conduit-like structures, open EC junctional complexes or by both pathways. Such studies will hopefully establish a framework that may lead to the development of therapeutic intervention for the treatment of neonatal meningitis and several other inflammatory conditions of the CNS.

描述（由申请人提供）：由机会致病微生物（例如白色念珠菌）产生的新生儿脑膜炎是一种炎症性疾病，可在出生后第一个月内发生，是早产儿和免疫功能低下婴儿神经退行性状态和发病的主要原因。新生儿脑膜炎是由于中枢神经系统、血脑屏障（BBB）和免疫系统发育不完全造成的。炎症条件下病原微生物和白细胞穿过血脑屏障的粘附和迁移的确切性质仍不清楚，这是现代医学非常感兴趣的一个问题。该研究计划将重点研究白色念珠菌和炎症白细胞在脑膜炎过程中对微生​​物做出反应时出现的粘附和迁移机制。我们的研究将在新生大鼠实验诱发脑膜炎的体内模型中进行。我们的假设表明，致病性酵母菌白色念珠菌最初会诱发脑膜血管的炎症状态。随后，白细胞粘附并穿过内皮细胞（EC）屏障，该屏障受到酵母细胞响应而局部释放的趋化物质的刺激。整个 BBB 粘附和迁移过程由包括 ICAM-1、PECAM-1 和 VCAM-1 在内的粘附分子通过跨细胞途径穿过 EC、通过细胞旁途径穿过 EC 连接复合物或通过两种机制来促进。我们该项目的具体目标是定义和比较白色念珠菌强毒株的粘附和迁移的光学显微镜、免疫组织化学、超微结构和免疫超微结构性质，以及炎性白细胞的不同主要亚群，包括中性粒细胞、单核细胞和淋巴细胞这是对新生大鼠酵母诱导的脑膜脑炎的反应。这将为我们研究粘附分子如何通过修饰的 EC 导管样结构、开放的 EC 连接复合体或通过专门的解剖学“大脑门户”调节致病性酵母细胞和白细胞跨 BBB 的附着和迁移奠定基础。两条途径。此类研究有望建立一个框架，从而开发治疗新生儿脑膜炎和中枢神经系统其他几种炎症性疾病的治疗干预措施。