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

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

项目成果

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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:
T-cell immunity to polyomavirus infection
T细胞对多瘤病毒感染的免疫
  • 批准号:
    8687581
  • 财政年份:
    2012
  • 资助金额:
    $ 43.09万
  • 项目类别:
T-cell immunity to polyomavirus infection
T细胞对多瘤病毒感染的免疫
  • 批准号:
    8515330
  • 财政年份:
    2012
  • 资助金额:
    $ 43.09万
  • 项目类别:

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