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Deciphering Early Stages of Polyomavirus CNS Pathogenesis and Immunity

破译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：
10785321
负责人：
Aron Eliot Lukacher
金额：
$ 8.68万
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：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2030-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10785321
关键词：
Acquired Immunodeficiency Syndrome Address Affinity Animal Model Autoimmune Biological Products Brain Brain Diseases CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Capsid Proteins Central Nervous System Diseases Central Nervous System Infections Cerebrum Complication Cryoelectron Microscopy Custom Demyelinations Development Disease Ependyma Epitopes Event Family Foundations Hematologic Neoplasms Heterogeneity Human Immune Immunity Immunologics Immunotherapeutic agent Incidence Individual Infection Inflammatory Invaded JC Virus Lesion Life Link Maintenance Maps Memory Modeling Mus Mutation Natural Immunity Pathogenesis Patients Polyomavirus Progressive Multifocal Leukoencephalopathy Reaction Resolution STAT1 gene Staging T cell response T-Lymphocyte Therapeutic Three-Dimensional Imaging Tropism Tysabri Variant Ventricular Virus Visualization brain parenchyma chemotherapeutic agent chronic infection drug withdrawal human pathogen image reconstruction immune modulating agents in vivo in vivo evaluation interleukin-21 mortality mouse polyomavirus multiple sclerosis patient natalizumab neuropathology neutralizing antibody next generation sequencing pathogen preservation tissue culture

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. Polyomaviruses are species-specific. Lack of a tractable animal model of polyomavirus-induced CNS disease is an acknowledged bottleneck to elucidating PML pathogenesis, the immunological 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. Using mouse polyomavirus (MuPyV), we developed a natural virus-host model of polyomavirus-associated CNS disease. In this R35 application, we plan to leverage our three recent key findings: (1) Mapping JCPyV-PML VP1 capsid protein mutations to MuPyV’s VP1 confers escape from virus- neutralizing antibodies (nAb) while preserving CNS tropism; (2) IL-21 produced by high-affinity anti-MuPyV CD4 T cells in the brain is required for formation and maintenance of MuPyV-specific brain resident-memory CD8 T cells (bTRM); and (3) STAT1-dependent innate immunity limits infection of the ventricular ependyma, a critical barrier to infection of the brain parenchyma. These findings lay the foundation for three key questions to be addressed here: (1) Is the ependyma the staging ground for polyomavirus invasion of the brain parenchyma?; (2) Does the integrity of the CD8 bTRM response to persistent infection depend on subset heterogeneity?; and (3) 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 intact mouse brains to visualize virus CNS entry and spread. Findings from these studies will answer fundamental questions about innate and adaptive immune control of polyomavirus CNS infection and conditions underlying dissemination of virus from the periphery into the brain before development of irreversible neuropathology.

摘要 JC多瘤病毒（JCPyV）是一种普遍存在的人类病原体，在人类中引起几种毁灭性的脑部疾病。免疫力低下的人。这些JCPyV相关CNS疾病中最值得注意的是经常是致命的脱髓鞘性脑疾病进行性多灶性白质脑病（PML）。PML，一种 cART前阶段的艾滋病定义性病变已成为患者危及生命的并发症接受用于自身免疫性和炎性疾病的免疫调节剂以及用于某些血液恶性肿瘤在迅速扩大的PML相关生物制剂清单中，那他珠单抗（Tysabri®）的发病率最高，是多发性硬化症（MS）患者的不祥后遗症，否则受益于使用该免疫调节剂显著减少复发。停药，作为PML的唯一治疗选择，常并发高死亡率的脑炎症反应。没有抗JCPyV剂是可用的。多瘤病毒是物种特异性的。缺乏易处理的动物模型，多瘤病毒诱导的CNS疾病是阐明PML发病机制的公认瓶颈，控制JCPyV免疫学机制，抑制多瘤病毒的药剂的体内评价在组织培养中复制，并揭示预示不可逆的JCPyV相关的早期事件。神经病理学使用小鼠多瘤病毒（MuPyV），我们开发了一种天然的病毒宿主模型，多瘤病毒相关的CNS疾病。在这个R35应用程序中，我们计划利用我们最近的三个关键结果：（1）将JCPyV-PML VP 1衣壳蛋白突变定位到MuPyV的VP 1上，使其能够逃避病毒- 中和抗体（nAb），同时保留CNS嗜性;（2）由高亲和力抗MuPyV产生的IL-21 脑中的CD 4 T细胞是形成和维持MuPyV特异性脑驻留记忆所必需的 CD 8 T细胞（bTRM）;（3）STAT 1依赖性先天免疫限制了心室室管膜的感染，脑实质感染的关键屏障。这些发现为三个关键问题奠定了基础，室管膜是否是多瘤病毒侵入大脑的舞台薄壁组织？(2)CD 8 bTRM对持续性感染反应的完整性是否取决于亚群异质性？和（3）T细胞缺乏是否为nAb逃逸病毒变体的生长打开了大门？的拟议中的研究将利用下一代测序的前沿进展来揭示罕见的VP 1 体内突变，定制冷冻EM图像重建方法以确定内源性VP 1 nAb表位和nAb逃逸机制，以及完整小鼠大脑的高分辨率3D成像，以可视化病毒CNS 进入和传播。这些研究的结果将回答关于先天和适应性的基本问题多瘤病毒CNS感染的免疫控制和病毒传播的基础条件在不可逆的神经病理学发展之前，将其从外周转移到脑中。