Li Cui, Huynh Nguyen P T, Schanz Steven J, Windrem Martha S, Goldman Steven A
Center for Translational Neurodegeneration and Regenerative Therapy, Shanghai Tongji Hospital Affiliated to Tongji University School of Medicine, Shanghai 200072, China.
Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester NY 14604, USA.
Brain. 2024 Dec 3;147(12):4131-4146. doi: 10.1093/brain/awae252.
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.
进行性多灶性白质脑病是一种发生于免疫抑制患者脑部的脱髓鞘感染性疾病，由嗜神经胶质多瘤病毒JCV介导。JCV在人类神经胶质祖细胞和星形胶质细胞中复制，这些细胞会经历病毒T抗原触发的有丝分裂，从而实现病毒复制。我们不禁要问，神经胶质细胞的增殖是否会加速JCV的传播。通过体外分析和JCV感染的人类神经胶质嵌合小鼠模型，我们发现正在分裂的人类星形胶质细胞比处于有丝分裂静止期的细胞更能支持JCV的繁殖。相应地，整体和单细胞RNA序列分析显示，JCV感染的神经胶质细胞在DNA损伤反应和转录调控途径方面表现出与细胞周期相关的差异破坏。在体内，用铜螯合剂诱导的脱髓鞘及其相关的神经胶质祖细胞动员极大地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已感染神经胶质细胞的死亡，这反映了显著的旁观者死亡。总之，这些数据表明，在进行性多灶性白质脑病中，JCV的传播可能会因神经胶质细胞分裂而加速。因此，疾病相关脱髓鞘伴有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，从而增强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。
