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 新型隐球菌是一种胶囊化的芽殖酵母， 免疫功能低下的人，尤其是艾滋病患者。虽然感染始于肺部， 隐球菌病通常表现为脑膜脑炎，这是最常见的感染之一， 中枢神经系统和艾滋病毒感染者死亡的主要原因。C. 新生儿穿过血脑屏障（BBB）被认为是新生儿脑血管病治疗中最关键的步骤之一。 隐球菌脑膜脑炎的发展。体外研究表明，C.新生儿可以 通过转胞吞作用穿过单层脑微血管内皮细胞（BMEC）， "特洛伊木马"路径。然而，在体内，BBB是由BMEC，周细胞， 星形胶质细胞末端足，和基底膜在一个精确的组织，这是目前不能被 在试管中重建。问题仍然是如何C。新生儿通过血脑屏障迁移到大脑， 体内以及潜在的机制是什么。回答这些问题对于理解 隐球菌的发病机制，因为脑侵犯是这种疾病的标志性特征， 脑膜脑炎是隐球菌病的主要和最致命的并发症。与此前相比， 体外研究没有考虑血管血流动力学，我们已经开发了一种新的体内模型 基于多种新方法的系统直接调查C.新生儿 vivo.在这个项目中，我们将使用这个在体系统来研究C穿越血脑屏障。neoformans通过 目的：1）研究C.新型人及其机制 在体内的潜在途径。2)研究"特洛伊木马"途径及其潜在机制 在体内脑部感染的过程中。3)探讨C.新型生物破坏了 体内BBB。4)确定各机制对C.新人类 在建议的工作结束时，我们将确定在体内的机制（S），其中C。新生 穿过BBB。这项研究中创造的知识将为治疗糖尿病提供新的潜在治疗靶点。 干预这种疾病。