A human-derived 3D brain organoid model to study JC virus infection.
A human-derived 3D brain organoid model to study JC virus infection.
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DOI：
10.1007/s13365-022-01062-7
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发表时间：
2022-03
影响因子：
3.2
通讯作者：
Pardo CA
中科院分区：
文献类型：
--
作者：
Barreras P;Pamies D;Monaco MC;Muñoz LS;Zhong X;Major EO;Hogberg HT;Hartung T;Pardo CA
进行性多灶性白质脑病（PML）是免疫抑制患者常见的神经系统并发症。PML是由JC病毒（JCV）引起的，JC病毒是一种嗜神经DNA多瘤病毒，感染少突胶质细胞和星形胶质细胞，引起炎症和脱髓鞘，导致神经功能障碍。由于缺乏体外或动物模型来研究疾病机制，PML的发病机制知之甚少，因为病毒仅最有效地感染人类细胞。我们开发了一种人源性脑器官型系统（也称为脑类器官）来模拟JCV感染。该模型是通过使用人类诱导的多能干细胞（iPSC）并在3D中培养它们来开发的，以生成包含神经元、星形胶质细胞和少突胶质细胞的器官型模型，该模型概括了人脑环境的各个方面。我们用JCV MAD 4菌株或PML患者的脑脊液感染脑类器官。在暴露后1、2和3周，通过qPCR、免疫荧光和电子显微镜评估类器官的感染证据。通过免疫细胞化学研究证实了JCV MAD 4株和PML CSF暴露的脑类器官中的JCV感染，证明了病毒抗原，并且电子显微镜显示了少突胶质细胞和星形胶质细胞核隔室中的病毒粒子。未观察到神经元感染的证据。在病毒暴露的类器官及其培养基中也通过JCV qPCR证明了感染。总之，JCV感染的脑类器官模型建立了适合于研究JCV感染机制和PML发病机制的人类模型，并可能有助于探索治疗方法。
Progressive multifocal leukoencephalopathy (PML) is a frequent neurological complication in immunosuppressed patients. PML is caused by the JC virus (JCV), a neurotropic DNA polyomavirus that infects oligodendrocytes and astrocytes, causing inflammation and demyelination which lead to neurological dysfunction. The pathogenesis of PML is poorly understood due to the lack of in vitro or animal models to study mechanisms of disease as the virus most efficiently infects only human cells. We developed a human-derived brain organotypic system (also called brain organoid) to model JCV infection. The model was developed by using human-induced pluripotent stem cells (iPSC) and culturing them in 3D to generate an organotypic model containing neurons, astrocytes, and oligodendrocytes which recapitulates aspects of the environment of the human brain. We infected the brain organoids with the JCV MAD4 strain or cerebrospinal fluid of a patient with PML. The organoids were assessed for evidence of infection by qPCR, immunofluorescence, and electron microscopy at 1, 2, and 3 weeks post-exposure. JCV infection in both JCV MAD4 strain and PML CSF-exposed brain organoids was confirmed by immunocytochemical studies demonstrating viral antigens and electron microscopy showing virion particles in the nuclear compartment of oligodendrocytes and astrocytes. No evidence of neuronal infection was visualized. Infection was also demonstrated by JCV qPCR in the virus-exposed organoids and their media. In conclusion, the brain organoid model of JCV infection establishes a human model suitable for studying the mechanisms of JCV infection and pathogenesis of PML and may facilitate the exploration of therapeutic approaches.
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DOI：
10.1038/s41582-020-00427-y
发表时间：
2021-01
期刊：
Nature reviews. Neurology
影响因子：
--
作者：
Cortese I;Reich DS;Nath A
通讯作者：
Nath A
影响因子：
15.9
作者：
Kondo, Yoichi;Windrem, Martha S.;Goldman, Steven A.
通讯作者：
Goldman, Steven A.
影响因子：
5.6
作者：
Kang, Ian;Smirnova, Lena;Hartung, Thomas
通讯作者：
Hartung, Thomas
影响因子：
5.4
作者：
Ravichandran, Veerasarny;Sabath, Bruce F.;Major, Eugene O.
通讯作者：
Major, Eugene O.
影响因子：
5.6
作者：
Chesnut M;Paschoud H;Repond C;Smirnova L;Hartung T;Zurich MG;Hogberg HT;Pamies D
通讯作者：
Pamies D