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）：我们已经描述了由JC病毒（JCV）感染的新型临床实体在免疫抑制个体中感染皮质锥体神经元。该患者出现了仅限于MRI上半球灰质的病变，患有失语症，进行性认知功能障碍和癫痫发作，并迅速致命的结果。我们称这种疾病JCV脑病（JCVE），因为它与胶质细胞的JCV感染引起的进行性多灶性白血病（PML）不同。 Mortem组织学评估首次证明了JCV对皮质锥体神经元的生产性和裂解感染。我们已经分析了从该患者大脑获得的JCVCV的JCVCPN1的JCV分子克隆的全长序列，该序列揭示了类似原型的调节区域（RR）和Angnoprotein Gene中的新型143 BP缺失。随后在其他三名PML患者的神经元或脑脊液中发现了CPN突变体。我们假设JCV序列的变化是该患者皮质锥体神经元的特异性感染。然而，神经元的JCVCPN1是否通过其RR，新型的Agnoprotein缺失或两者都可能使神经元的生长成为可能。此外，我们假设在其他个体中也可能发生JCV感染皮质神经元的感染，包括位于灰色白色交界处或灰质内的脱髓鞘病变的PML患者。最后，我们假设位于海马中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特定目的：目标1）在体外目的中表征JCVCPN1的宿主细胞范围2）确定Agnoprotein缺失和类似原型的RR对JCVCPN1 Inter Aim In In In Inter Aim Inter Aim Inter Aim Inter Aim Inter Aim Inter Aim Inter Aim Inter Aim In 3）表征来自PML患者的档案样本中皮质锥体神经元的JCV感染的流行率，并使用免疫组织化学和激光捕获的微分解目的确定CPN1突变的症状4）研究Hippocapal pyramidal神经元的JCV感染在不受欢迎的患者中，并且在不受欢迎的患者中施加了孔或骨骼的患者。癫痫公共卫生相关性：JC病毒感染神经胶质细胞并通常引起大脑白质疾病，称为进行性多焦点白细胞术。我们已经描述了由JC病毒变体感染皮质金字塔神经元引起的新型临床实体。我们称这种疾病仅限于大脑的灰质，JCV脑病（JCVE）。我们将表征这种独特的JC病毒在体外变体的发病机理，并定义免疫抑制个体中金字塔神经元的JCV感染率。我们还将研究海马神经元的JCV感染在具有顽固性癫痫发作或海马硬化症的老年受试者的免疫能力的人中的作用。