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.

计划概要 进行性多灶性白质脑病 (PML) 是威胁患者生命的主要并发症 患有艾滋病和正在接受自身免疫性疾病免疫治疗的患者，例如多发性硬化症 硬化症、克罗恩病、严重斑块状银屑病、系统性红斑狼疮、血液学 恶性肿瘤和类风湿性关节炎。矛盾的是，这种疾病是由一个普通人引起的 中枢神经系统（CNS）失去正常免疫监视后的多瘤病毒。 我们对支撑这一现象的基础生物学的理解存在几个重大差距 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参与其中。二、病毒的控制机制 持久性尚未明确定义，但病毒启动子发生变化（原型为 PML 型）和 病毒 microRNA 的调控被认为对于过渡到裂解阶段至关重要。第三， 病毒传播到中枢神经系统和中枢神经系统内部的机制尚不清楚。根据我们最近的工作 我们假设游离病毒以及包裹在细胞外囊泡中的病毒从 肾到脉络丛和脑膜室，其中 CPE 细胞的复制提供了 EV介导的脑实质侵入的手段。一旦进入大脑细胞外囊泡 介导的传播可能在感染传播中发挥主要作用，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 进一步加深我们对病毒传染性传播的基本机制的理解，并利用 识别生物标志物的信息，这些生物标志物可以在易于接近的区域中早期预测 PML 早在病毒有机会传播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。