Progressive Multifocal Leukoenephalopathy: Endemic Viruses and Lethal Brain Disease

进行性多灶性白质脑病：地方性病毒和致命性脑病

• 批准号: 10393583
• 负责人: Walter J Atwood
• 金额: $ 83.61万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10393583
• 关键词: Acquired Immunodeficiency Syndrome; Anatomy; Autoimmune Diseases; Biological Markers; Biology; Bone Marrow; Brain; Brain Diseases; Cells; Central Nervous System Diseases; Chronic small plaque psoriasis; Clinic; Complication; Crohn' s disease; Development; Disease; Functional disorder; Hematologic Neoplasms; Human; Immune system; Immunologic Surveillance; Immunotherapy; Individual; Infection; JC Virus; Kidney; Lead; Life; Lytic Phase; Mediating; Meningeal; MicroRNAs; Multiple Sclerosis; Neuraxis; Patients; Play; Polyomavirus; Population; Progressive Multifocal Leukoencephalopathy; Regulation; Rheumatoid Arthritis; Role; Structure of choroid plexus; Systemic Lupus Erythematosus; Translating; Viral; Virus; Vision; Work; base; biomarker identification; brain parenchyma; extracellular vesicles; macroglia; novel strategies; prevent; programs; promoter; receptor

Program Summary Progressive Multifocal Leukoencephalopathy (PML) is a major life threatening complication in patients with AIDS and in patients undergoing immunotherapy for autoimmune diseases such as multiple sclerosis, Crohn's disease, severe plaque psoriasis, systemic lupus erythematosis, hematologic malignancies, and rheumatoid arthritis. The disease is paradoxically caused by a common human polyomavirus following the loss of normal immune surveillance of the central nervous system (CNS). There are several major gaps in our understanding of the basic biology that underpins the development of PML. First, the anatomical site of virus persistence is not known but kidney, bone marrow, and brain have all been postulated to be involved. Second, the mechanisms that govern viral persistence are not well defined but changes in the viral promoter (archetype to PML-type) and regulation of a viral microRNA are thought to be critical for transition to the lytic phase. Third, the mechanisms of viral spread to the CNS and within the CNS are not known. Based on our recent work we hypothesize that free virus as well as virus enclosed in extracellular vesicles spreads from the kidney to the choroid plexus and meningeal compartments where replication in CPE cells provides the means for EV mediated invasion of brain parenchyma. Once in the brain extracellular vesicle mediated spread is likely to play the major role in spreading the infection because macroglia lack the principle cellular receptors to support infection by free virus. Our vision for the R35 application is to further our understanding of these basic mechanisms of infectious spread of virus and to use the information to identify biomarkers that can predict PML early and in easily accessible compartments well before the virus has a chance to spread to the CNS. The work should also lead to the development of novel strategies to treat and prevent PML.

节目概要 进行性多灶性白质脑病（PML）是患者的主要危及生命的并发症 艾滋病患者和接受自身免疫性疾病免疫治疗的患者， 硬化症、克罗恩病、重度斑块状银屑病、系统性红斑狼疮、血液学 恶性肿瘤和类风湿性关节炎。这种疾病是由一个普通人引起的， 在中枢神经系统（CNS）的正常免疫监视丧失后，多瘤病毒引起的。 在我们对基础生物学的理解上有几个主要的差距， PML的发展。首先，病毒持续存在的解剖部位尚不清楚，但肾脏、骨骼 骨髓和大脑都被认为与此有关。第二，控制病毒的机制 持久性没有很好地定义，但病毒启动子的变化（原型到PML型）和 病毒微小RNA的调控被认为是向裂解相转变的关键。三是 病毒传播到CNS和在CNS内的机制尚不清楚。根据我们最近的研究 我们假设游离病毒和包封在细胞外囊泡中的病毒都是从 肾至脉络丛和脑膜隔室，在那里CPE细胞中的复制提供了 EV介导的脑实质侵入的手段。一旦进入脑细胞外囊泡 介导的传播可能在传播感染中起主要作用，因为大胶质细胞缺乏 支持游离病毒感染的主要细胞受体。我们对R35应用的愿景是 进一步了解病毒传染性传播的基本机制， 识别可早期预测PML的生物标志物的信息，并在易于获取的区域中 在病毒有机会扩散到中枢神经系统之前这项工作还应导致 开发治疗和预防PML的新策略。