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:
- 金额:$ 43.09万
- 依托单位:
- 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:
- 关键词:Acquired Immunodeficiency SyndromeAdultAnimal ModelAnti-Inflammatory AgentsAntibody RepertoireAntibody ResponseAutoimmuneAutoimmunityB-Lymphocyte EpitopesBiologicalBiological ProductsBloodBrainBrain DiseasesCD8-Positive T-LymphocytesCapsid ProteinsCellsCentral Nervous System DiseasesCentral Nervous System InfectionsCentral Nervous System Viral DiseasesCerebrumChoroid Plexus EpitheliumClinicalClinical TrialsComplicationCryoelectron MicroscopyCustomDemyelinationsDepressed moodDevelopmentDiagnosisDiseaseEngineeringEpendymaEpitopesEventFamilyFoundationsGrantHematologic NeoplasmsHumanImmuneImmune EvasionImmunityImmunocompromised HostImmunoglobulin GImmunologicsImmunomodulatorsImmunosuppressionImmunotherapeutic agentIncidenceIndividualInfectionInflammatoryIntegrin alpha4JC VirusKidneyLeadLesionLifeLinkMapsMediatingModelingMolecularMonoclonal AntibodiesMorbidity - disease rateMusMutant Strains MiceMutationNatural ImmunityNeurotropismParentsPathogenesisPatientsPlasma ExchangePolyomavirusPolyomavirus InfectionsPopulationProcessProgressive Multifocal LeukoencephalopathyReactionRelapseReportingResistanceResolutionRiskSTAT1 geneSeriesSiteStagingStretchingSystemic Lupus ErythematosusT-LymphocyteTestingTherapeuticThree-Dimensional ImagingTropismTysabriUrinary tractUrineValidationVariantVentricularViralViral PathogenesisViremiaVirusVirus Diseasesbrain parenchymachemotherapeutic agentclinical practicedrug candidatedrug withdrawalhuman pathogenhuman viromeimage reconstructionimprovedin vivoin vivo evaluationmacrogliamortalitymouse polyomavirusmultiple sclerosis patientmutantnatalizumabneuropathologyneutralizing antibodynext generation sequencingpathogenpre-clinicalpreservationresponsesmall moleculesubventricular zonetissue 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. 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.
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。缺乏易处理的多瘤病毒诱导的CNS疾病的动物模型,
阐明PML发病机制的公认瓶颈,控制JCPyV的免疫学机制,
在组织培养物中抑制多瘤病毒复制的试剂的体内评价,以及揭示
预示着不可逆的JCPyV相关神经病理学-这一更新申请的重点。使用小鼠
为了研究多瘤病毒(MuPyV),我们开发了多瘤病毒相关CNS疾病的天然病毒宿主模型。在
在这一更新申请中,我们将利用在母R 01补助金下取得的两项关键发现:(1)绘制
JCPyV-PML VP 1衣壳蛋白突变为MuPyV的VP 1,可逃避病毒中和抗体
(nAb)同时保持CNS向性;和(2)STAT 1依赖性先天免疫限制了
脑室室管膜是随后脑实质感染的关键屏障。这两项发现,
(1)在本更新申请中提出的两个关键问题奠定了基础:(1)
室管膜是多瘤病毒侵入脑实质的舞台?(2)T细胞
缺乏为nAb逃逸病毒变体的生长打开了大门?拟议的研究将利用
下一代测序的前沿进展,以揭示体内罕见的VP 1突变,定制冷冻EM
确定内源性VP 1 nAb表位和nAb逃逸机制的图像重建方法,以及
小鼠大脑的高分辨率3D成像,以可视化病毒CNS进入和扩散。这些调查结果
研究将回答有关JCPyV的先天和适应性免疫控制的基本问题,
用于鉴别具有JCPyV相关CNS疾病风险患者的改进标准。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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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:
$ 43.09万 - 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:
10785321 - 财政年份:2022
- 资助金额:
$ 43.09万 - 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:
$ 43.09万 - 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:
$ 43.09万 - 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:
$ 43.09万 - 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:
$ 43.09万 - 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:
$ 43.09万 - 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:
$ 43.09万 - 项目类别:
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