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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：
8788562
负责人：
Igor J Koralnik
金额：
$ 38.06万
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 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8788562
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 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 Untranslated RNA 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

描述（由申请人提供）：我们描述了一种由JC病毒（JCV）感染免疫抑制个体皮质锥体神经元引起的新型临床实体。该患者在MRI上表现为局限于半球灰质的病变，出现失语症、进行性认知功能障碍和癫痫发作，并出现快速致死性结局。我们称这种疾病为JCV脑病（JCVE），因为它不同于由JCV感染神经胶质细胞引起的进行性多灶性白质脑病（PML）。尸检组织学评价首次证明了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脑中获得的JCV分子克隆的全长序列，JCVCPN 1，其揭示了原型样调节区（RR）和Agnoprotein基因中的新的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。我们推测，在JCV序列的变化是负责在这个病人的皮质锥体神经元的特异性感染。然而，JCVCPN 1在神经元中的生长是否可能是由于其RR，新的Agnoprotein缺失，或两者兼而有之，仍不清楚。此外，我们推测，JCV感染的皮质神经元也可能发生在其他个人，包括在PML患者的脱髓鞘病变位于灰白色交界处或灰质内。最后，我们假设位于海马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的发生。为了检验这些假设，我们将追求以下一组具体目标：目的1）鉴定JCVCPN 1的体外宿主细胞范围目的2）确定Agnoprotein缺失和archetype-like RR对JCVCPN 1体外表型的贡献目的3）描述PML患者存档样本中皮质锥体神经元JCV感染的患病率，并使用免疫组织化学鉴定CPN 1突变目的4）研究免疫抑制个体和海马硬化或难治性癫痫患者海马锥体神经元的JCV感染