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Molecular pathology in viral neurophathogenesis of developmental brain disorders

发育性脑疾病病毒性神经病理发生的分子病理学

基本信息

批准号：
15390126
负责人：
TSUTSUI Yoshihiro
金额：
$ 9.02万
依托单位：
Hamamatsu University School of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-15390126/
关键词：
viral encephalopathy cytomegalovirus developmental disorders neural stem progenitor cells latent infection transgenic mice embryonic stem cells neurosheres 神経幹細胞大脳スライス培養持続感染

项目摘要

Developing brains are highly susceptible to cytomegalovirus infection, causing developmental brain disorders. Brain disorders are also induced by reactivation of the virus in immune-compromised patients. In order to certify the hypothesis that latent CMV infection occurs in the brains, neonatal mice were infected with murine CMV (MCMV) and raised for a long time and removed the brains. Reactivation was observed in the brain slice cultures. For further analysis, nestin-promoter-GFP inserted transgenic (Tg) mice (provided Dr.H.Okano, Keio Univ.) were latently infected with MCMV. Immature neural cells cultures in the presence of ganciclovir (GCV), then, neurospheres were isolated. We demonstrated that infective virus is released from the neurospheres by plaque assay. This fact indicates that latent infection may occur in neural stem/progenitor cells. We have showed that neurons tend to become persistent infection and that neuronal expression of the early gene e1-promoter was observed in the transgenic mice. We investigated the effect of MCMV infection on the expression of NMDA rece ptors that are essential for the plasticity of synapses and neuronal excito-toxicity. We showed that expression of NMDA receptors were reduced by MCMV infection, probably relating to establish persistent infection and causing functional disorders. Furthermore, in contrast to neural stem/progenitor cells, we showed that embryonic stem (ES) cells are not susceptible to MCMV infection but acquired the susceptibility during the glial differentiation.

发育中的大脑非常容易受到巨细胞病毒的感染，从而导致发育中的大脑疾病。免疫受损患者的病毒重新激活也会导致脑部疾病。为了证实CMV潜伏感染存在于脑内的假说，用小鼠巨细胞病毒(MCMV)感染新生小鼠，长期饲养取脑。在脑片培养中观察到再激活。为进一步分析，插入Nestin启动子-GFP的转基因(TG)小鼠(由庆应义乌大学H.Okano博士提供。)都潜伏着感染了MCMV。在更昔洛韦(GCV)存在下培养未成熟神经细胞，然后分离神经球。我们通过空斑实验证明了感染性病毒从神经球中释放出来。这一事实表明，潜伏感染可能发生在神经干细胞/祖细胞中。我们已经证明了神经元倾向于持续感染，并且在转基因小鼠中观察到了早期基因E1-启动子的神经元表达。我们研究了MCMV感染对突触可塑性和神经元兴奋性毒性所必需的NMDA受体表达的影响。我们发现MCMV感染降低了NMDA受体的表达，这可能与持续感染和引起功能障碍有关。此外，与神经干细胞/祖细胞相比，我们发现胚胎干细胞对MCMV感染不敏感，但在神经胶质分化过程中获得了敏感性。