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The study for the persistent infection of cytomegalovirus in the developing cerebral neuron

巨细胞病毒在发育中脑神经元持续感染的研究

基本信息

批准号：
18500278
负责人：
KOSUGI Isao
金额：
$ 2.57万
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 (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

项目摘要

Cytomegalovirus (CMV) is the leading viral cause of developmental brain disorders in humans. During murine CMV (MCMV) infection of newborn mice, viral early-antigen (El, product of el gene ; M112/113) persisted in neurons of hippocampus (HP) and cerebral cortex (CX) after disappearance of El from non-neuronal cells. Furthermore, neuron-specific activation of MCMV-el promoter (el-pro) in our transgenic mice suggests that a unique el-pro activation likely occurs in developing neurons and may be an important factor for viral neuropathogenesis.We have constructed recombinant MCMV (rMCMV1373 or rMCMV448), which expresses EGFP as a reporter under control of full-length (1373 nt) or truncated (448 nt) el-pro fragment. We have investigated differences in el-pro activation between neurons and non-neuronal cells, in situ, during rMCMV infection of developing mouse brains and primary neuronal cultures.Among any brains infected with wild-type MCMV or rMCMVs, at 7 days-post-infection (dpi) viral an … More tigens (IE1, IE3 and E1) were expressed not only in non-neuronal cells of periventricular area (PV) but also in neurons of HP and CX. At 11 dpi antigens disappeared from PV but persisted exclusively in neurons. In rMCMV 1373-infected brains, kinetics of EGFP expression was the same as that of El. While in rMCMV 448-infected brains EGFP was clearly detected in non-neuronal cells until 7dpi, but not in neurons at any time despite the enough neuronal E1 expression. In rMCMV 1373-infected primary neuronal cultures, EGFP was also preferentially detected in neurons, but very scarcely in rMCMV 448-infected neurons.Our results suggest that IE3-binding sites in truncated el-pro fragment is involved in sufficient el-pro activation in non-neuronal cells as reported previously. However, upstream region from -449 to -1373 nt in full-length el-pro fragment seems to be necessary for neuron-specific activation of el-pro. It is supposed that this unique neuronal el-pro activation may be closely associated with viral neurotropism and neuropathogenesis. Less

巨细胞病毒（CMV）是人类大脑发育障碍的主要病毒原因。在小鼠CMV（MCMV）感染新生小鼠期间，病毒早期抗原（El，el基因的产物；M112/113）在El从非神经元细胞中消失后持续存在于海马（HP）和大脑皮层（CX）的神经元中。此外，我们的转基因小鼠中 MCMV-el 启动子 (el-pro) 的神经元特异性激活表明，独特的 el-pro 激活可能发生在发育中的神经元中，并且可能是病毒神经发病的重要因素。我们构建了重组 MCMV（rMCMV1373 或 rMCMV448），其在全长控制下表达 EGFP 作为报告基因（1373 nt）或截短的（448 nt）el-pro 片段。我们研究了在 rMCMV 感染发育中的小鼠大脑和原代神经元培养物期间，原位神经元和非神经元细胞之间 el-pro 激活的差异。在感染野生型 MCMV 或 rMCMV 的任何大脑中，在感染后 7 天 (dpi)，病毒和老虎 (IE1、IE3 和 E1) 不仅在不仅存在于脑室周围区域 (PV) 的非神经元细胞，而且存在于 HP 和 CX 的神经元中。 11 dpi 时，抗原从 PV 中消失，但仅在神经元中持续存在。在rMCMV 1373感染的大脑中，EGFP表达的动力学与E1的相同。而在 rMCMV 448 感染的大脑中，直到 7dpi 之前，在非神经元细胞中都可以清楚地检测到 EGFP，但尽管有足够的神经元 E1 表达，但在任何时候都没有在神经元中检测到 EGFP。在 rMCMV 1373 感染的原代神经元培养物中，EGFP 也优先在神经元中检测到，但在 rMCMV 448 感染的神经元中很少检测到。我们的结果表明，如先前报道的，截短的 el-pro 片段中的 IE3 结合位点参与了非神经元细胞中充分的 el-pro 激活。然而，全长el-pro片段中从-449到-1373nt的上游区域似乎对于el-pro的神经元特异性激活是必需的。据推测，这种独特的神经元el-pro激活可能与病毒的趋神经性和神经发病机制密切相关。较少的