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Pathogenesis of a JC Virus Variant in Pyramidal Neurons

JC 病毒变异体在锥体神经元中的发病机制

基本信息

批准号：
8289758
负责人：
Igor J Koralnik
金额：
$ 32.04万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-02-15 至 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8289758
关键词：
Acquired Immunodeficiency Syndrome Adult Antibodies Astrocytes Atrophic Autoimmune Diseases Blood Brain CYP11B1 gene Capsid Proteins Cells Cerebrospinal Fluid Clinical Code Demyelinating Diseases Demyelinations Development Disease Elderly Encephalopathies Evaluation Fatal Outcome Functional RNA Genes Genome Gray unit of radiation dose Growth Hematologic Neoplasms Hippocampus (Brain)Human Immunocompetent Immunocompromised Host Immunohistochemistry Impaired cognition In Vitro Individual Infection Inflammatory Intractable Epilepsy JC Virus Kidney Large T Antigen Lead Length Lesion Lytic Phase Magnetic Resonance Imaging Malignant neoplasm of lung Molecular Cloning Mutation Neuroglia Neurologic Dysfunctions Neurons Nucleic Acid Regulatory Sequences Oligodendroglia Organ Transplantation Pathogenesis Patients Phenotype Polyomavirus Prevalence Progressive Aphasias Progressive Multifocal Leukoencephalopathy Recording of previous events Role Sampling Sclerosis Seizures Testing Time Transplant Recipients Tropism Urine Variant Virus Virus Diseases White Matter Disease chemotherapy ds-DNA granule cell gray matter hippocampal pyramidal neuron immunosuppressed laser capture microdissection mutant novel patient population

项目摘要

DESCRIPTION (provided by applicant): We have described a novel clinical entity caused by JC virus (JCV) infection of cortical pyramidal neurons in an immunosuppressed individual. This patient presented with lesions restricted to the hemispheric gray matter on MRI, developed aphasia, progressive cognitive dysfunction and seizures and had a rapid fatal outcome. We called this disease JCV encephalopathy (JCVE), since it is distinct from Progressive Multifocal Leukoencephalopathy (PML), caused by JCV infection of glial cells. Post mortem histological evaluation demonstrated for the first time a productive and lytic infection of cortical pyramidal neurons by JCV. We have analyzed the full length sequence of a molecular clone of JCV obtained from the brain of this patient, JCVCPN1, which revealed an archetype-like regulatory region (RR), and a novel 143 bp deletion in the Agnoprotein gene. The CPN mutant was subsequently found in the neurons or cerebrospinal fluid of three other patients with PML. We hypothesize that changes in JCV sequence are responsible for the specific infection of cortical pyramidal neurons in this patient. However, whether JCVCPN1 growth in neurons is made possible by its RR, the novel Agnoprotein deletion, or both, remains unclear. Furthermore, we postulate that JCV infection of cortical neurons may also occur in other individuals, including in PML patients with demyelinating lesions located at the gray white- junction or within the gray matter. Finally, we hypothesize that other pyramidal neurons, located in the hippocampus may also be infected by JCV variants, which could lead to the development of seizures. To test these hypotheses, we will pursue the following set of Specific Aims: Aim 1) Characterize the host cell range of JCVCPN1 in vitro Aim 2) Determine the contributions of the Agnoprotein deletion and archetype-like RR to the phenotype of JCVCPN1 in vitro Aim 3) Characterize the prevalence of JCV infection of cortical pyramidal neurons in archival samples from PML patients and identify the CPN1 mutation using immunohistochemistry and laser capture microdissection Aim 4) Investigate JCV infection of hippocampal pyramidal neurons in immunosuppressed individuals and in patients with hippocampal sclerosis or intractable epilepsy PUBLIC HEALTH RELEVANCE: JC virus infects glial cells and typically causes a disease of the white matter of the brain, called Progressive Multifocal Leukoencephalopathy. We have described a novel clinical entity caused by a JC virus variant infecting cortical pyramidal neurons. We called this disease, restricted to the gray matter of the brain, JCV encephalopathy (JCVE). We will characterize the pathogenesis of this unique JC virus variant in vitro and define the prevalence of JCV infection of pyramidal neurons in immunosuppressed individuals. We will also investigate the role of JCV infection of hippocampal neurons in immunocompetent people with intractable seizures or elderly subjects with hippocampal sclerosis.

描述（由申请人提供）：我们描述了免疫抑制个体中皮质锥体神经元的 JC 病毒（JCV）感染引起的新的临床实体。该患者在 MRI 上表现出仅限于半球灰质的病变，出现失语、进行性认知功能障碍和癫痫发作，并迅速致命。我们将这种疾病称为 JCV 脑病 (JCVE)，因为它与由神经胶质细胞 JCV 感染引起的进行性多灶性白质脑病 (PML) 不同。尸检组织学评估首次证明了 JCV 对皮质锥体神经元的生产性和溶解性感染。我们分析了从该患者大脑中获得的 JCV 分子克隆 JCVCPN1 的全长序列，该序列揭示了一个类似原型的调节区 (RR)，以及 Agno Protein 基因中的一个新的 143 bp 缺失。随后在另外三名 PML 患者的神经元或脑脊液中发现了 CPN 突变体。我们假设 JCV 序列的变化导致了该患者皮质锥体神经元的特异性感染。然而，JCVCPN1 在神经元中的生长是否是通过其 RR、新型 Agno 蛋白缺失或两者共同实现的，仍不清楚。此外，我们推测皮质神经元的 JCV 感染也可能发生在其他个体中，包括灰白交界处或灰质内脱髓鞘病变的 PML 患者。最后，我们假设位于海马体的其他锥体神经元也可能被 JCV 变体感染，这可能导致癫痫发作。为了检验这些假设，我们将追求以下一组具体目标：目标 1) 体外表征 JCVCPN1 的宿主细胞范围目标 2) 确定 Agno蛋白缺失和原型样 RR 对体外 JCVPN1 表型的贡献目标 3) 表征来自 PML 患者和患者的档案样本中皮质锥体神经元 JCV 感染的患病率使用免疫组织化学和激光捕获显微切割识别 CPN1 突变目标 4) 研究免疫抑制个体和海马硬化或顽固性癫痫患者海马锥体神经元的 JCV 感染公共卫生相关性：JC 病毒感染神经胶质细胞，通常会引起大脑白质疾病，称为进行性多灶性白质脑病。我们描述了一种由感染皮质锥体神经元的 JC 病毒变种引起的新临床实体。我们将这种局限于大脑灰质的疾病称为 JCV 脑病 (JCVE)。我们将在体外描述这种独特的 JC 病毒变种的发病机制，并确定免疫抑制个体中锥体神经元 JCV 感染的流行情况。我们还将研究 JCV 感染对患有顽固性癫痫发作的免疫功能正常的人或患有海马硬化的老年受试者的海马神经元的作用。