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.

项目概要 新型隐球菌是一种封装的芽殖酵母，可导致危及生命的疾病 免疫功能低下的个体，尤其是艾滋病患者。尽管感染是从肺部开始的， 隐球菌病通常表现为脑膜脑炎，这是最常见的感染之一 中枢神经系统，是艾滋病毒感染者死亡的主要原因。 C. 迁徙 新型隐球菌穿过血脑屏障（BBB）被认为是实现这一目标的最关键步骤之一。 隐球菌性脑膜脑炎的发展。体外研究表明，新型隐球菌可以 通过转胞吞作用跨过单层脑微血管内皮细胞 (BMEC) “特洛伊木马”途径。然而，在体内 BBB 是一个复杂的组织，由 BMEC、周细胞、 星形胶质细胞的末端脚和精确组织中的基底膜，目前还无法确定 在体外重新创建。关于新型隐球菌如何穿过 BBB 迁移到大脑的问题仍然存在。 体内以及潜在的机制是什么。回答这些问题是理解的基础 隐球菌发病机制，因为脑侵袭是这种疾病的标志性特征， 脑膜脑炎是隐球菌病主要且最致命的并发症。与之前相比 体外研究没有考虑血管血流动力学，我们开发了一种新颖的体内模型 基于多种新方法的系统直接研究新型隐球菌的脑侵入 体内。在这个项目中，我们将使用这个体内系统来研究新型隐球菌对 BBB 的穿越 解决以下目标：1）表征新型隐球菌的转胞吞作用及其机制 体内这条途径的基础。 2）探究“特洛伊木马”途径及底层机制 在体内脑部感染期间。 3) 描述新型隐球菌损害的机制 体内BBB。 4)确定每种机制对新型隐球菌脑侵袭的相对贡献。 在拟议工作结束时，我们将确定新型隐球菌的体内机制 穿过 BBB。这项研究中创造的知识将为以下疾病提供新的潜在治疗靶点： 针对这种疾病进行干预。