Leukocyte Transmigration in Neonatal Candida Meningitis

描述(申请人提供)：由机会致病微生物，如酵母白色念珠菌引起的新生儿脑膜炎是一种炎症性疾病，可发生在出生后的第一个月，是早产儿和免疫功能低下婴儿神经退化状态和发病率的主要原因。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所致。致病微生物和白细胞在炎症状态下跨越血脑屏障的黏附和迁移的确切性质尚不清楚，这是现代医学非常感兴趣的问题。这项研究计划将重点放在白念珠菌和炎性白细胞在脑膜炎过程中对微生物的反应中出现的黏附和移行机制。我们的研究将在实验诱导的新生大鼠脑膜炎的体内模型中进行。我们的假设是致病的白色念珠菌最初在脑膜血管中诱导炎症状态。随后，白细胞附着并穿过内皮细胞(EC)屏障，这是由于酵母菌细胞局部释放趋化物质所致。包括ICAM-1、PECAM-1和VCAM-1在内的黏附分子通过跨细胞途径或通过细胞旁途径通过EC连接复合体，或通过两种机制促进整个跨越血脑屏障的黏附和迁移过程。我们项目的具体目标将是定义和比较白念珠菌毒力株的粘附性和移行的光镜、免疫组织化学、超微结构和免疫结构性质，以及在新生大鼠酵母诱导的脑膜脑炎反应中出现的不同的主要炎性白细胞亚群，包括中性粒细胞、单核细胞和淋巴细胞。这将为我们研究黏附分子如何调节致病酵母细胞和白细胞跨血脑屏障的附着和迁移奠定基础，这些黏附分子是通过特殊的解剖学“通往大脑的网关”，通过修饰的EC管状结构、开放的EC连接复合体或通过这两条途径来调节致病酵母细胞和白细胞的附着和迁移。这些研究有望建立一个框架，可能导致开发治疗干预措施，治疗新生儿脑膜炎和其他几种中枢神经系统炎症性疾病。

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.