Progressive multifocal leukoencephalopathy is a demyelinating infection of the immunosuppressed brain, mediated by the gliotropic polyomavirus JCV. JCV replicates in human glial progenitor cells and astrocytes, which undergo viral T-antigen-triggered mitosis, enabling viral replication. We asked whether JCV spread might therefore be accelerated by glial proliferation. Using both in vitro analysis and a human glial chimeric mouse model of JCV infection, we found that dividing human astrocytes supported JCV propagation to a substantially greater degree than did mitotically quiescent cells. Accordingly, bulk and single-cell RNA-sequence analysis revealed that JCV-infected glia differentially manifested cell cycle-linked disruption of both DNA damage response and transcriptional regulatory pathways. In vivo, JCV infection of humanized glial chimeras was greatly accentuated by cuprizone-induced demyelination and its associated mobilization of glial progenitor cells. Importantly, in vivo infection triggered the death of both uninfected and infected glia, reflecting significant bystander death. Together, these data suggest that JCV propagation in progressive multifocal leukoencephalopathy might be accelerated by glial cell division. As such, the accentuated glial proliferation attending disease-associated demyelination might provide an especially favourable environment for JCV propagation, thus potentiating oligodendrocytic bystander death and further accelerating demyelination in susceptible hosts.

中文翻译：

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JC 病毒的传播因神经胶质细胞复制和脱髓鞘相关的神经胶质细胞增殖而增强


进行性多灶性白质脑病是由嗜胶质性多瘤病毒 JCV 介导的免疫抑制脑脱髓鞘感染。JCV 在人神经胶质祖细胞和星形胶质细胞中复制，它们经历病毒 T 抗原触发的有丝分裂，从而实现病毒复制。我们询问神经胶质细胞增殖是否会因此加速 JCV 的传播。使用体外分析和 JCV 感染的人神经胶质嵌合小鼠模型，我们发现分裂的人星形胶质细胞比有丝分裂静止细胞在更大程度上支持 JCV 增殖。因此，大量和单细胞 RNA 序列分析显示，JCV 感染的神经胶质细胞差异表现为 DNA 损伤反应和转录调节途径的细胞周期相关破坏。在体内，铜酮诱导的神经胶质细胞脱髓鞘及其相关的神经胶质祖细胞动员大大加剧了人源化神经胶质嵌合体的 JCV 感染。重要的是，体内感染引发了未感染和感染的神经胶质细胞的死亡，反映了重要的旁观者死亡。总之，这些数据表明，神经胶质细胞分裂可能会加速 JCV 在进行性多灶性白质脑病中的传播。因此，疾病相关脱髓鞘引起的神经胶质细胞增殖加剧可能为 JCV 传播提供特别有利的环境，从而加剧少突胶质细胞旁观者死亡并进一步加速易感宿主的脱髓鞘。