Leukocyte Transmigration in Neonatal Candida Meningitis

描述（由申请人提供）：由白色念珠菌等机会致病性微生物产生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行性状态和发病率的主要原因。新生儿脑膜炎可归因于中枢神经系统、血脑屏障（BBB）和免疫系统发育不全。在炎症条件下，致病生物和白细胞在血脑屏障上的粘附和转运的确切性质尚不清楚，这是现代医学非常感兴趣的问题。本研究项目将重点研究白色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粘附和转运机制。我们的研究将在新生大鼠实验性脑膜炎的体内模型中进行。我们的假设表明，致病性酵母白色念珠菌最初诱导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，受到局部释放的化学引诱物质的刺激，以响应酵母细胞。包括ICAM-1、PECAM-1和VCAM-1在内的粘附分子通过跨细胞途径或通过EC连接复合物通过细胞旁途径或通过两种机制促进了整个血脑屏障的粘附和转运过程。我们项目的具体目标是定义和比较白念珠菌毒力菌株粘附和迁移的光镜、免疫组织化学、超微结构和免疫超结构性质，以及新生大鼠对酵母诱导的脑膜脑炎的反应中出现的不同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连接复合物或通过两种途径通过专门的解剖学“通往大脑的通道”调节致病酵母细胞和白细胞在血脑屏障上的附着和转运奠定基础。这些研究有望建立一个框架，可能导致治疗新生儿脑膜炎和其他几种中枢神经系统炎症性疾病的治疗干预的发展。

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.