The study of virus-induced brain disorders by a model system using neural stem cells

巨细胞病毒（CMV）是人类大脑发育障碍最常见的感染性原因。神经干/祖细胞（NSPCs）的感染似乎是导致大脑异常的主要原因。先前，我们报道了从胎鼠大脑中制备的NSPCs允许小鼠CMV （MCMV）感染，并且病毒感染抑制了它们的生长和迁移，并抑制了它们的分化，特别是神经元分化（Lab Invest 2000）。然而，在MCMV感染过程中，病毒基因如何引起NSPCs的紊乱还有待阐明。在这项研究中，我们试图建立一个模型系统来研究MCMV基因对NSPCs生长和分化的影响。直接早期1 （ie1）基因通过逆转录病毒载体转入NSPCs。ie1的转导抑制了NSPCs的生长。当NSPCs被诱导分化时，与对照组相比，ie1转导的NSPCs中早期神经元标志物微管相关蛋白5 （MAP5）的表达减少。这些数据表明，MCMV IE1蛋白破坏了NSPCs的自我更新能力和多能性，而这些能力是NSPCs的主要功能。病毒基因转导至NSPCs可能为阐明人类先天性巨细胞病毒感染脑异常的发病机制提供一个模型系统。

Cytomegalovirus (CMV) is the most frequent infectious cause of development disorders of the brain in humans. Infection of the neural stem/progenitor cells (NSPCs) seems to be primarily responsible for the generation of the brain abnormalities. Previously, we reported that NSPCs prepared from fetal mouse brains were permissive for murine CMV (MCMV) infection, and that the virus infection suppressed their growth and migration, and inhibited their differentiation, especially neuronal differentiation (Lab Invest 2000). However, it needs to be elucidated how viral genes cause the disorder of NSPCs during MCMV infection. In this study we tried to establish a model system for investigating the effects of MCMV genes on the growth and differentiation of NSPCs. An immediate early 1 (ie1) gene was transduced into NSPCs via a retrovirus vector. The transduction of ie1 suppressed the growth of NSPCs. When NSPCs were induced to differentiate, in the ie1-transduced NSPCs the expression of microtubules-associated protein 5 (MAP5), an early neuronal marker, was decreased as compared with control. These data suggest that MCMV IE1 protein disrupts the ability of self-renewal and multi-potency which are the principal functions of NSPCs. The transduction of viral genes into NSPCs might provide a model system for clarifying the pathogenesis of the brain abnormalities in congenital CMV infection in humans.