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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

基本信息

批准号：
10133156
负责人：
Aron Eliot Lukacher
金额：
$ 38.62万
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：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10133156
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 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 Rheumatism 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

项目摘要

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