Progressive Multifocal Leukoenephalopathy: Endemic Viruses and Lethal Brain Disease

计划摘要 进行性多灶性白质脑病(PML)是威胁患者生命的主要并发症 艾滋病患者和正在接受免疫治疗的自身免疫性疾病患者，如多发性 硬化症、克罗恩病、严重斑块型银屑病、系统性红斑狼疮、血液病 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 在失去对中枢神经系统(CNS)的正常免疫监视后，出现多瘤病毒。 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位置未知，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 持久性没有被很好地定义，但病毒启动子(原型到PML类型)和 对病毒微小RNA的调节被认为是向裂解期过渡的关键。第三， 病毒传播到中枢神经系统和中枢神经系统内的机制尚不清楚。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小泡中的病毒从 肾到脉络丛和脑膜室，在那里CPE细胞的复制提供 EV介导的脑实质侵袭手段。一次进入脑细胞外小泡 介导性传播可能在传播感染中起主要作用，因为大胶质细胞缺乏 支持由游离病毒感染的主要细胞受体。我们对R35应用程序的愿景是 进一步加深我们对病毒传染性传播的这些基本机制的理解，并利用 用于识别生物标记物的信息，这些生物标记物可以在容易接近的间隔内早期预测PML 在病毒有机会传播到中枢神经系统之前。这项工作也应该导致 开发治疗和预防PML的新策略。

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.