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:
- 金额:$ 8.68万
- 依托单位:
- 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:
- 关键词:Acquired Immunodeficiency SyndromeAddressAffinityAnimal ModelAutoimmuneBiological ProductsBrainBrain DiseasesCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCD8B1 geneCapsid ProteinsCentral Nervous System DiseasesCentral Nervous System InfectionsCerebrumComplicationCryoelectron MicroscopyCustomDemyelinationsDevelopmentDiseaseEpendymaEpitopesEventFamilyFoundationsHematologic NeoplasmsHeterogeneityHumanImmuneImmunityImmunologicsImmunotherapeutic agentIncidenceIndividualInfectionInflammatoryInvadedJC VirusLesionLifeLinkMaintenanceMapsMemoryModelingMusMutationNatural ImmunityPathogenesisPatientsPolyomavirusProgressive Multifocal LeukoencephalopathyReactionResolutionSTAT1 geneStagingT cell responseT-LymphocyteTherapeuticThree-Dimensional ImagingTropismTysabriVariantVentricularVirusVisualizationbrain parenchymachemotherapeutic agentchronic infectiondrug withdrawalhuman pathogenimage reconstructionimmune modulating agentsin vivoin vivo evaluationinterleukin-21mortalitymouse polyomavirusmultiple sclerosis patientnatalizumabneuropathologyneutralizing antibodynext generation sequencingpathogenpreservationtissue 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。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Polyomavirus Wakes Up and Chooses Neurovirulence.
- DOI:10.3390/v15102112
- 发表时间:2023-10-18
- 期刊:
- 影响因子:0
- 作者:Butic AB;Spencer SA;Shaheen SK;Lukacher AE
- 通讯作者:Lukacher AE
Merkel Cell Polyomavirus Large T Antigen Induces Cellular Senescence for Host Growth Arrest and Viral Genome Persistence through Its Unique Domain.
- DOI:10.3390/cells12030380
- 发表时间:2023-01-20
- 期刊:
- 影响因子:6
- 作者:Pham, Alexander M.;Ortiz, Luz E.;Lukacher, Aron E.;Kwun, Hyun Jin
- 通讯作者:Kwun, Hyun Jin
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Aron Eliot Lukacher其他文献
Aron Eliot Lukacher的其他文献
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{{ truncateString('Aron Eliot Lukacher', 18)}}的其他基金
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
- 批准号:
10449608 - 财政年份:2022
- 资助金额:
$ 8.68万 - 项目类别:
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
- 批准号:
10610484 - 财政年份:2022
- 资助金额:
$ 8.68万 - 项目类别:
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
- 批准号:
10365345 - 财政年份:2016
- 资助金额:
$ 8.68万 - 项目类别:
Pathogenesis of Mouse Polyomavirus-associated CNS Demyelination
小鼠多瘤病毒相关中枢神经系统脱髓鞘的发病机制
- 批准号:
9185385 - 财政年份:2016
- 资助金额:
$ 8.68万 - 项目类别:
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:
8853962 - 财政年份:2014
- 资助金额:
$ 8.68万 - 项目类别:
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 - 财政年份:2014
- 资助金额:
$ 8.68万 - 项目类别:
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:
9244865 - 财政年份:2014
- 资助金额:
$ 8.68万 - 项目类别:
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:
10133156 - 财政年份:2014
- 资助金额:
$ 8.68万 - 项目类别:
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