Human glial chimeric mice reveal astrocytic dependence of JC virus infection
Human glial chimeric mice reveal astrocytic dependence of JC virus infection
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DOI：
10.1172/jci76629
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发表时间：
2014-12-01
影响因子：
15.9
通讯作者：
Goldman, Steven A.
中科院分区：
文献类型：
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作者：
Kondo, Yoichi;Windrem, Martha S.;Goldman, Steven A.
进行性多灶性白质脑病(PML)是一种由人类嗜胶质JC病毒(JCV)感染引发的脱髓鞘疾病。由于该病毒对人类的选择性，目前尚无动物模型可用于研究JCV的发病机制。为了解决这个问题，我们通过将人神经胶质前体细胞(GPC)移植到新生免疫缺陷和髓鞘缺陷小鼠中，开发了人源化白质小鼠。脑内注射JCV导致了这些嵌合小鼠的感染和随后的脱髓鞘。人星形胶质细胞和星形胶质细胞比少突胶质细胞更容易感染，病毒复制主要发生在星形胶质细胞和星形胶质细胞，而不是少突胶质细胞，而少突胶质细胞表达早期病毒T抗原，并表现为凋亡性死亡。将人GM植入正常有髓细胞和免疫缺陷小鼠体内，产生了人化白质，这对人类星形胶质细胞和GPC是嵌合的。JCV在这些小鼠体内有效地繁殖，这表明星形胶质细胞感染足以使JCV传播。测序显示JCV衣壳蛋白VP1在感染后发生渐进性突变，提示PML可能随着活动性感染而演变。这些结果表明，JCV感染的主要中枢神经系统靶点是星形胶质细胞和GPC，感染与渐进性突变有关，脱髓鞘是继T抗原触发的少突胶质细胞凋亡之后的第二次发生。更广泛地说，这项研究提供了一个模型，通过它进一步评估人类特有的嗜胶性病毒的生物学和治疗。
Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease triggered by infection with the human gliotropic JC virus (JCV). Due to the human-selective nature of the virus, there are no animal models available to investigate JCV pathogenesis. To address this issue, we developed mice with humanized white matter by engrafting human glial progenitor cells (GPCs) into neonatal immunodeficient and myelin-deficient mice. Intracerebral delivery of JCV resulted in infection and subsequent demyelination of these chimeric mice. Human GPCs and astrocytes were infected more readily than oligodendrocytes, and viral replication was noted primarily in human astrocytes and GPCs rather than oligodendrocytes, which instead expressed early viral T antigens and exhibited apoptotic death. Engraftment of human GM in normally myelinated and immunodeficient mice resulted in humanized white matter that was chimeric for human astrocytes and GPCs. JCV effectively propagated in these mice, which indicates that astroglial infection is sufficient for JCV spread. Sequencing revealed progressive mutation of the JCV capsid protein VP1 after infection, suggesting that PML may evolve with active infection. These results indicate that the principal CNS targets for JCV infection are astrocytes and GPCs and that infection is associated with progressive mutation, while demyelination is a secondary occurrence, following T antigen-triggered oligodendroglial apoptosis. More broadly, this study provides a model by which to further assess the biology and treatment of human-specific gliotropic viruses.