In vivo mechanisms of brain invasion by Cryptococcus neoformans

新型隐球菌脑侵袭的体内机制

• 批准号: 9912711
• 负责人: Meiqing Shi
• 金额: $ 37.79万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-22 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9912711
• 关键词: Acquired Immunodeficiency Syndrome; Address; Animal Model; Animals; Astrocytes; Basement membrane; Behavior; Binding; Biological Models; Blood - brain barrier anatomy; Blood Circulation; Blood Vessels; Brain; CD44 gene; Cause of Death; Cells; Central Nervous System Infections; Cessation of life; Characteristics; Complex; Complication; Cryptococcosis; Cryptococcus; Cryptococcus neoformans; Cultured Cells; Data; Development; Disease; Encapsulated; Endothelium; Equus caballus; Exocytosis; Extravasation; Flow Cytometry; HIV; Human; Hyaluronic Acid; Immunocompromised Host; In Vitro; Individual; Infection; Intervention; Invaded; Knowledge; Lead; Life; Ligands; Lung; Meningoencephalitis; Microglia; Modeling; Nerve; Neurotropism; Nonlytic; Organism; Pathogenesis; Pathway interactions; Patients; Pericytes; Phagocytes; Phagocytosis; Pneumonia; Prevention; Prevention strategy; Respiratory System; Role; Saccharomycetales; Supporting Cell; System; Therapeutic; Time; Tissues; Vascular Endothelial Cell; Virulence; Virulence Factors; Work; Yeasts; base; blood damage; blood-brain barrier crossing; brain endothelial cell; capsule; foot; fungus; in vivo; in vivo Model; insight; intravital microscopy; macrophage; migration; monocyte; monolayer; mortality; mutant; novel; novel strategies; pathogen; pathogenic fungus; receptor; shear stress; therapeutic target; time use; transcytosis

Project Summary Cryptococcus neoformans is an encapsulated budding yeast that causes a life-threatening illness in immunocompromised individuals, especially in AIDS patients. Although the infection starts in the lung, cryptococcosis commonly presents as meningoencephalitis, which is one of the most common infections of the central nervous system and a leading cause of death in HIV-infected individuals. Transmigration of C. neoformans across the blood-brain barrier (BBB) is believed to be one of the most critical steps in the development of cryptococcal meningoencephalitis. In vitro studies have shown that C. neoformans can transmigrate across a monolayer of brain microvascular endothelial cells (BMECs) through transcytosis and “Trojan horse” pathways. However, in vivo the BBB is a complex tissue that consists of BMECs, pericytes, astrocyte end feet, and a basement membrane in a precise organization, which cannot at present be recreated in vitro. Questions still remain as to how C. neoformans migrates to the brain across the BBB in vivo and what is the underlying mechanism(s). Answering these questions is fundamental for understanding cryptococcal pathogenesis, because brain invasion is the hallmark feature of this disease and meningoencephalitis is the major and most lethal complication of cryptococcosis. In contrast to previous in vitro studies that did not account for vascular haemodynamics, we have developed a novel in vivo model system based on multiple novel approaches to directly investigate the brain invasion by C. neoformans in vivo. In this project, we will use this in vivo system to study traversal of the BBB by C. neoformans by addressing the following aims: 1) To characterize the transcytosis of C. neoformans and the mechanism underlying this pathway in vivo. 2) To investigate the “Trojan horse” pathway and the underlying mechanism during brain infection in vivo. 3) To characterize the mechanism(s) whereby C. neoformans damages the BBB in vivo. 4) To determine the relative contribution of each mechanism to brain invasion by C. neoformans. At the end of the proposed work, we will have identified the in vivo mechanism(s) by which C. neoformans traverses the BBB. The knowledge created in this study will provide new potential therapeutic targets of intervention for this disease.

项目摘要 加密赛车是一种封装的萌芽酵母，会导致威胁生命的疾病 免疫功能低下的个体，特别是在艾滋病患者中。尽管感染始于肺部，但 隐球菌病通常表现为脑膜脑炎，这是最常见的感染之一 艾滋病毒感染者的中枢神经系统和主要死亡原因。 C. 跨血脑屏障（BBB）的新羊角人被认为是最关键的步骤之一 隐球菌脑膜脑炎的发展。体外研究表明，新生梭菌可以 跨脑膜内皮细胞（BMEC）跨移民跨移民。 “特洛伊木马”道路。但是，在体内，BBB是一个复杂的组织，由BMEC，周细胞， 星形胶质细胞末端的脚和精确组织中的地下室膜，目前不能 在体外重新创建。关于梭状芽胞杆菌如何跨BBB迁移到大脑中的问题仍然存在 体内以及什么是基本机制。回答这些问题是理解的基础 隐球菌发病机理，因为大脑侵袭是该疾病的标志特征， 脑膜脑炎是隐球菌病的主要和最致命的并发症。与以前的 未考虑血管血流动力学的体外研究，我们开发了一种新型体内模型 基于多种新型方法直接研究Neoformans脑侵袭的系统 体内。在这个项目中，我们将使用此体内系统来研究C. Neoformans的BBB遍历 解决以下目的：1）表征新梭菌的转介症和机制 在体内这条途径的基础。 2）调查“特洛伊木马”途径和基本机制 在体内脑感染期间。 3）表征C. Neoformans损害的机制 BBB在体内。 4）确定每种机制对脑脑浸润的相对贡献。 在拟议的工作结束时，我们将确定C. Neoformans的体内机制 穿越BBB。这项研究中创建的知识将提供新的潜在治疗靶标 干预这种疾病。