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

• 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
• 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

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.

摘要 进行性多灶性白质脑病（PML）是一种危及生命的脱髓鞘脑部疾病， JC多瘤病毒（JCPyV）是一种普遍存在的人类病原体，没有 抗JCPyV剂是可用的。在不断扩大的PML相关生物制剂纲要中， 那他珠单抗的发病率最高（1-2%），是多发性硬化症（MS）的一种不祥并发症 使用该免疫调节剂可显著减少复发，从而使患者受益。药物 停药是PML的唯一治疗选择，通常并发高死亡率的脑炎症， 反应此外，最近已经描述了三种非PML JCPyV-CNS疾病。缺乏一个听话的 多瘤病毒诱导的CNS疾病的动物模型是阐明PML的公认瓶颈 控制JCPyV的发病机制和免疫机制（两者对于识别PML风险至关重要 因子），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价。使用 小鼠多瘤病毒（MuPyV），我们开发了一种多瘤病毒相关的天然病毒宿主模型， 脱髓鞘在R 01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- 记忆性CD 8 T细胞（bTRM）群体。TRM作为非再循环细胞散布于全身， 在那里它们提供了抵抗再感染的前线防御。我们对TRM生物学的理解主要来自于 分析粘膜屏障中的这些细胞;对TRM在非粘膜感染部位的了解少得多， 特别是那些具有大量不可再生电池的电池（例如，CNS）。我们发现了一个关键的联系 CD 4 T细胞与功能性MuPyV特异性CD 8 bTRM的分化之间的关系。我们的初步数据显示 强有力的科学前提，我们的中心假设，IL-21是“帮助”提供的CD 4 T细胞， 产生MuPyV特异性CD 8 bTRM。CD 4 T细胞不足和IL-21信号转导缺陷分别导致 表达TRM表型的抗病毒CD 8 T细胞丧失，并且在没有再补给的情况下无法在脑中存活 从循环。CD 4 T细胞-无助于抗病毒的CD 8 T细胞的基因表达途径分析 持续性MuPyV脑炎揭示了IL-21和Notch信号通路的失调， 通过STAT 3进行潜在收敛。MuPyV特异性CD 8 bTRM表达功能性Notch受体，其 在没有CD 4 T细胞帮助的情况下，活化减少。Notch受体最近被报道 支持建立组织驻留记忆CD 8 T细胞。对于特异性目的1，我们假设IL-21 是由CD 4 T细胞提供的帮助的主要成分，以指导脑浸润性CD 8 T细胞的分化。 细胞进入TRM。对于特异性目的2，我们假设IL-21和Notch信号通过STAT 3协同作用， 活化以产生CD 8 bTRM。如果这些假设被证明是正确的，它们将提供重要的见解， 维持和维持多瘤病毒CNS感染的免疫控制的机制。