A Mouse Model to Define Immunovirologic Determinants of Polyomavirus CNS Disease

定义多瘤病毒中枢神经系统疾病免疫病毒学决定因素的小鼠模型

基本信息

批准号：
9920216
负责人：
Aron Eliot Lukacher
金额：
$ 38.63万
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：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9920216
关键词：
AIDS/HIV problem Affect Animal Model Anti-Inflammatory Agents Antiviral Agents Autoimmunity Biological Biological Products Biological Response Modifiers Biology Blood Circulation Brain Brain Diseases CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cells Central Nervous System Diseases Central Nervous System Infections Central Nervous System Viral Diseases Cerebrum Characteristics Clinical Trials Complication Cues Data Demyelinations Dependence Depressed mood Disease Encephalitis Encephalopathies Evolution Failure Family Gene Expression Hematologic Neoplasms Highly Active Antiretroviral Therapy Human Hydrocephalus Immune Immunologic Deficiency Syndromes Immunologics Immunomodulators Immunotherapeutic agent Incidence Individual Infection Inflammation Inflammatory Integrin alpha4 JC Virus Leukoencephalopathy Life Ligands Link Lung Lymphocytic Infiltrate Maintenance Memory Meningitis Modeling Monitor Monoclonal Antibodies Mucous Membrane Multiple Sclerosis Mus Neuroglia Neuropathy Notch Signaling Pathway Parents Pathogenesis Pathway Analysis Patients Phenotype Plasma Exchange Polyomavirus Population Progressive Multifocal Leukoencephalopathy Reaction Relapse Relapsing-Remitting Multiple Sclerosis Reporting Risk Factors Role STAT3 gene Signal Transduction Site Source Survivors T cell differentiation Testing Therapeutic Time Tissues Tysabri Viral Virus Work chemotherapy clinical practice drug withdrawal granule cell human pathogen immunological status immunomodulatory therapies in vivo in vivo evaluation insight interleukin-21 receptor mortality mouse model mouse polyomavirus multiple sclerosis patient natalizumab notch protein novel pathogen pre-clinical response tissue culture transcriptome white matter

项目摘要

ABSTRACT Progressive Multifocal Leukoencephalopathy (PML) is a life-threatening demyelinating brain disease in immune-compromised individuals caused by the JC polyomavirus (JCPyV), a ubiquitous human pathogen. No anti-JCPyV agents are available. Among the expanding compendium of PML-associated biologics, natalizumab has the highest incidence (1-2%) and is an ominous complication 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. Moreover, three non-PML JCPyV-CNS diseases have recently been described. Lack of a tractable animal model of polyomavirus-induced CNS disease is a well-recognized bottleneck to elucidating PML pathogenesis and the immunological mechanisms that control JCPyV (both essential for identifying PML risk factors), and in vivo evaluation of antiviral agents that inhibit polyomavirus replication in tissue culture. Using mouse polyomavirus (MuPyV), we developed a natural virus-host model of polyomavirus-associated demyelination. In work supported by the parent R01, we found a sizeable MuPyV-specific, brain resident- memory CD8 T cell (bTRM) population. TRM are disseminated throughout the body as non-recirculating cells, where they provide frontline defense against reinfection. Our understanding of TRM biology comes largely from analysis of these cells in mucosal barriers; far less is understood about TRM in nonmucosal sites of infection, particularly those with large numbers of nonrenewable cells (e.g., CNS). We discovered a critical connection between CD4 T cells and differentiation of functional MuPyV-specific CD8 bTRM. Our preliminary data provide strong scientific premise for our central hypothesis that IL-21 is the “help” proffered by CD4 T cells for generating MuPyV-specific CD8 bTRM. CD4 T cell insufficiency and IL-21 signaling-deficiency each resulted in loss of antiviral CD8 T cells expressing a TRM phenotype and inability to survive in the brain without resupply from the circulation. Gene expression pathway analyses of CD4 T cell-unhelped antiviral CD8 T cells during persistent MuPyV encephalitis revealed dysregulation of IL-21 and Notch signaling pathways, and their potential convergence via STAT3. MuPyV-specific CD8 bTRM express functional Notch receptors, whose activation is diminished in the absence of CD4 T cell help. Notch receptors have recently been reported to support establishment of tissue-resident memory CD8 T cells. For Specific Aim 1, we hypothesize that IL-21 is a major component of the help provided by CD4 T cells to guide differentiation of brain-infiltrating CD8 T cells into TRM. For Specific Aim 2, we hypothesize that IL-21 and Notch signaling cooperate via STAT3 activation to generate CD8 bTRM. If these hypotheses prove correct, they will provide essential insights into the mechanisms involved in maintaining and sustaining immunologic control of polyomavirus CNS infection.

抽象的进行性多灶性白细胞症（PML）是一种威胁生命的脱髓鞘脑疾病由无处不在的人类病原体JC多瘤病毒（JCPYV）引起的免疫强化个体。不可以使用抗jcpyv代理。在PML相关生物制剂的扩展纲要中， Natalizumab的事件最高（1-2％），是多发性硬化症的不祥并发症（MS）否则使用这种免疫调节剂复发中急剧减少而受益的患者。药品戒断是PML的唯一热选择，通常会因高性分性脑炎症而变得复杂反应。此外，最近已经描述了三种非PML JCPYV-CNS疾病。缺乏障碍多符号病毒诱导的中枢神经系统疾病的动物模型是一种公认的瓶颈，以阐明PML 发病机理和控制JCPYV的免疫学机制（既可以识别PML风险因素），以及在组织培养中抑制多瘤病毒复制的抗病毒剂的体内评估。使用小鼠多瘤病毒（MUPYV），我们开发了一种天然病毒宿主模型，该模型是多瘤病毒相关的脱髓鞘。在父母R01支持的工作中，我们发现了一个相当大的mupyv特异性大脑居民 - 记忆CD8 T细胞（BTRM）种群。 TRM作为非循环细胞在整个人体中传播，他们提供对重新感染的前线防御。我们对TRM生物学的理解主要来自分析这些细胞在粘膜屏障中的分析；关于TRM在非肿瘤感染部位的理解少得多，特别是那些具有大量不可再生细胞的人（例如CNS）。我们发现了一个关键的联系 CD4 T细胞与功能MUPYV特异性CD8 BTRM的分化。我们的初步数据提供对于我们的中心假设，即IL-21是CD4 T细胞证明的“帮助”的强烈科学前提生成MUPYV特异性CD8 BTRM。 CD4 T细胞功能不全和IL-21信号失调导致表达TRM表型的抗病毒CD8 T细胞的丧失，无法在大脑中生存而无需补给从循环中。基因表达途径分析CD4 T细胞无螺旋抗病毒CD8 T细胞的基因表达途径。持续的mupyv脑炎显示IL-21和Notch信号通路的失调及其失调通过STAT3的潜在收敛。 MUPYV特异性CD8 BTRM Express功能缺口受体，谁在没有CD4 T细胞帮助的情况下，激活减少。 Notch接收器最近已报告支持建立组织居民记忆CD8 T细胞。对于特定目标1，我们假设IL-21 是CD4 T细胞提供的帮助的主要组成部分，以指导脑渗透CD8 T的分化细胞进入TRM。对于特定目标2，我们假设通过STAT3进行IL-21和Notch信号合作激活以生成CD8 BTRM。如果这些假设被证明是正确的，它们将为维持和维持对多瘤病毒CNS感染的免疫控制的机制。