Pathogenesis of a JC Virus Variant in Pyramidal Neurons

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，它揭示了一个类似原型的调节区 (RR)，以及 Agno Protein 基因中一个新的 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，我们假设皮质神经元的 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。为了测试这些假设，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 PML 患者档案样本中皮质锥体神经元 JCV 感染的流行情况，并使用免疫组织化学和激光鉴定 CPN1 突变捕获显微解剖目标 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

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