Defining Early Stages of Polyomavirus CNS Pathogenesis and Immunity

定义多瘤病毒中枢神经系统发病机制和免疫的早期阶段

基本信息

批准号：
10365345
负责人：
Aron Eliot Lukacher
金额：
$ 43.09万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-01 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10365345
关键词：
Acquired Immunodeficiency Syndrome Adult Animal Model Anti-Inflammatory Agents Antibody Repertoire Antibody Response Autoimmune Autoimmunity B-Lymphocyte Epitopes Biological Biological Products Blood Brain Brain Diseases CD8-Positive T-Lymphocytes Capsid Proteins Cells Central Nervous System Diseases Central Nervous System Infections Central Nervous System Viral Diseases Cerebrum Choroid Plexus Epithelium Clinical Clinical Trials Complication Cryoelectron Microscopy Custom Demyelinations Depressed mood Development Diagnosis Disease Engineering Ependyma Epitopes Event Family Foundations Grant Hematologic Neoplasms Human Immune Immune Evasion Immunity Immunocompromised Host Immunoglobulin G Immunologics Immunomodulators Immunosuppression Immunotherapeutic agent Incidence Individual Infection Inflammatory Integrin alpha4 JC Virus Kidney Lead Lesion Life Link Maps Mediating Modeling Molecular Monoclonal Antibodies Morbidity - disease rate Mus Mutant Strains Mice Mutation Natural Immunity Neurotropism Parents Pathogenesis Patients Plasma Exchange Polyomavirus Polyomavirus Infections Population Process Progressive Multifocal Leukoencephalopathy Reaction Relapse Reporting Resistance Resolution Risk STAT1 gene Series Site Staging Stretching Systemic Lupus Erythematosus T-Lymphocyte Testing Therapeutic Three-Dimensional Imaging Tropism Tysabri Urinary tract Urine Validation Variant Ventricular Viral Viral Pathogenesis Viremia Virus Virus Diseases brain parenchyma chemotherapeutic agent clinical practice drug candidate drug withdrawal human pathogen human virome image reconstruction improved in vivo in vivo evaluation macroglia mortality mouse polyomavirus multiple sclerosis patient mutant natalizumab neuropathology neutralizing antibody next generation sequencing pathogen pre-clinical preservation response small molecule subventricular zone tissue culture

Acquired Immunodeficiency Syndrome Adult Animal Model Anti-Inflammatory Agents Antibody Repertoire Antibody Response Autoimmune Autoimmunity B-Lymphocyte Epitopes Biological Biological Products Blood Brain Brain Diseases CD8-Positive T-Lymphocytes Capsid Proteins Cells Central Nervous System Diseases Central Nervous System Infections Central Nervous System Viral Diseases Cerebrum Choroid Plexus Epithelium Clinical Clinical Trials Complication Cryoelectron Microscopy Custom Demyelinations Depressed mood Development Diagnosis Disease Engineering Ependyma Epitopes Event Family Foundations Grant Hematologic Neoplasms Human Immune Immune Evasion Immunity Immunocompromised Host Immunoglobulin G Immunologics Immunomodulators Immunosuppression Immunotherapeutic agent Incidence Individual Infection Inflammatory Integrin alpha4 JC Virus Kidney Lead Lesion Life Link Maps Mediating Modeling Molecular Monoclonal Antibodies Morbidity - disease rate Mus Mutant Strains Mice Mutation Natural Immunity Neurotropism Parents Pathogenesis Patients Plasma Exchange Polyomavirus Polyomavirus Infections Population Process Progressive Multifocal Leukoencephalopathy Reaction Relapse Reporting Resistance Resolution Risk STAT1 gene Series Site Staging Stretching Systemic Lupus Erythematosus T-Lymphocyte Testing Therapeutic Three-Dimensional Imaging Tropism Tysabri Urinary tract Urine Validation Variant Ventricular Viral Viral Pathogenesis Viremia Virus Virus Diseases brain parenchyma chemotherapeutic agent clinical practice drug candidate drug withdrawal human pathogen human virome image reconstruction improved in vivo in vivo evaluation macroglia mortality mouse polyomavirus multiple sclerosis patient mutant natalizumab neuropathology neutralizing antibody next generation sequencing pathogen pre-clinical preservation response small molecule subventricular zone tissue culture

展开

项目摘要

ABSTRACT JC polyomavirus (JCPyV), a ubiquitous human pathogen, causes several devastating brain diseases in immune compromised individuals. The most notable of these JCPyV-associated CNS diseases is the frequently fatal demyelinating brain disease progressive multifocal leukoencephalopathy (PML). PML, an AIDS-defining lesion in the pre-cART epoch, has emerged as a life-threatening complication in patients receiving immunomodulatory agents for autoimmune and inflammatory disorders and treatment for certain hematological malignancies. Among the rapidly expanding list of PML-associated biologics, natalizumab (Tysabri®) has the highest incidence and is an ominous sequela for multiple sclerosis (MS) patients who otherwise benefit from dramatic reductions in relapses using this immunomodulatory agent. Drug withdrawal, the only therapeutic option for PML, is often complicated by a high-mortality cerebral inflammatory reaction. No anti-JCPyV agents are available. Lack of a tractable animal model of polyomavirus-induced CNS disease is an acknowledged bottleneck to elucidating PML pathogenesis, timmunological mechanisms that control JCPyV, in vivo evaluation of agents that inhibit polyomavirus replication in tissue culture, and uncovering early events that presage irreversible JCPyV-associated neuropathology – the focus of this renewal application. Using mouse polyomavirus (MuPyV), we developed a natural virus-host model of polyomavirus-associated CNS disease. In this renewal application, we will leverage two key findings made under the parent R01 grant: (1) Mapping JCPyV-PML VP1 capsid protein mutations to MuPyV’s VP1 confers escape from virus-neutralizing antibodies (nAb) while preserving CNS tropism; and (2) STAT1-dependent innate immunity limits infection of the ventricular ependyma, a critical barrier to subsequent brain parenchymal infection. Both findings, which parallel those of JCPyV, lay the foundation for the two key questions raised in this renewal application: (1) Is the ependyma the staging ground for polyomavirus invasion of the brain parenchyma?; and (2) Does T cell deficiency open the door for outgrowth of nAb-escape virus variants? The proposed studies will make use of cutting edge advances in next-generation sequencing to uncover rare VP1 mutations in vivo, custom cryo EM image reconstruction approaches to define endogenous VP1 nAb epitopes and nAb escape mechanisms, and high-resolution 3D imaging of mouse brains to visualize viral CNS entry and spread. Findings from these studies will answer fundamental questions about innate and adaptive immune control of JCPyV and potentially improve criteria for identifying patients at risk for JCPyV-associated CNS diseases.

抽象的 JC多瘤病毒（JCPYV）是一种无处不在的人类病原体，引起了几种毁灭性的脑部疾病免疫受损的个体。这些JCPYV相关的中枢神经系统疾病中最明显的是 PML，一个艾滋病定义的病变在卡特前时期已成为患者的生命并发症接受免疫调节剂用于自身免疫和炎症性疾病，并治疗某些血液学恶性肿瘤。在迅速扩展的PML相关生物制剂清单中，Natalizumab （tysabri®）发病率最高，是多发性硬化症患者（MS）患者的续集否则，使用这种免疫调节剂中的复发中的急剧减少受益。戒毒， PML的唯一热选择，通常会因高病态性脑炎症反应而变得复杂。不可以使用抗jcpyv代理。缺乏多瘤病毒诱导的中枢神经系统疾病的可拖动动物模型是一种承认瓶颈阐明了PML发病机理，控制JCPYV的Timmunologicy机制，体内评估抑制组织培养中多层病毒复制的药物，并发现早期事件预售不可逆的JCPYV相关神经病理学 - 该更新应用的重点。使用鼠标多瘤病毒（MUPYV），我们开发了一种与多瘤病毒相关的中枢神经系统疾病的天然病毒宿主模型。在此续订申请，我们将利用父级R01授予下的两个关键发现：（1）映射 JCPYV-PML VP1 CAPSID蛋白突变，供MUPYV的VP1承认从病毒中和抗体中逃脱（nab）在保存中枢神经系统的最大性时；（2）STAT1依赖性的先天免疫学限制了感染心室室室室，这是随后脑实质感染的关键障碍。两个发现，哪个 JCPYV的那些，为在此续签应用中提出的两个关键问题奠定了基础：（1）是 despandyma是脑实质侵入多甲状腺病毒的阶段地面？（2）T细胞缺陷为NAB-ESCAPE病毒变体的生长打开了大门吗？拟议的研究将利用尖端的下一代测序进展，以发现体内罕见的VP1突变，自定义冷冻em 图像重建方法定义内源VP1 NAB表位和NAB逃生机制，以及小鼠大脑的高分辨率3D成像可视化病毒中枢神经系统的进入和扩散。这些发现研究将回答有关JCPYV的先天和适应性免疫控制的基本问题提高确定与JCPYV相关的中枢神经系统疾病风险的患者的标准。