Fritschy J M, Brandner S, Aguzzi A, Koedood M, Luscher B, Mitchell P J
Institutes of Molecular Biology, University of Zurich, CH-8057 Zurich, Switzerland.
J Neurosci. 1996 Apr 1;16(7):2275-82. doi: 10.1523/JNEUROSCI.16-07-02275.1996.
Human cytomegalovirus (HCMV) can cause debilitating, sometimes fatal, opportunistic infections in congenitally infected infants and in immunodeficient individuals such as patients with the acquired immunodeficiency syndrome (AIDS). Molecular mechanisms that determine cell type specificity of HCMV infection and latency are poorly understood. We recently described a transgenic mouse model for analysis of HCMV major immediate-early (IE) promoter regulation and showed that sites of IE promoter activity during murine embryogenesis correlate with known target tissues of congenital HCMV infection in human fetuses (Koedood et al., 1995). Among various permissive human tissues, the brain is a site where HCMV infections can be devastating. Here, we have used immunohistochemical double-labeling analysis to identify specific cell types with HCMV-IE promoter activity in brains of transgenic mice at several postnatal stages. IE promoter activity was restricted to some endothelial cells, ependymal cells, choroid plexus epithelia, and neurons at discrete locations in the forebrain, brainstem, and cerebellum. Endothelial cells and neurons with activity were proportionately more abundant in neonatal than in adult brains. Although the IE promoter was normally silent in most astrocytes, activity was strongly induced in reactive astrocytes in response to a neocortical stab lesion. The findings support a model, consistent with clinical literature on HCMV encephalitis, whereby tissue damage and gliosis caused by HCMV infection of endothelial and ependymal cells progressively renders adjacent permissive neurons and reactive astrocytes accessible to infection. This transgenic model system should facilitate identification of factors that regulate the HCMV IE promoter with regard to infection permissivity and reactivation from latency.
人类巨细胞病毒（HCMV）可在先天性感染的婴儿以及免疫缺陷个体（如获得性免疫缺陷综合征患者）中引发使人虚弱、有时甚至致命的机会性感染。目前，对于决定HCMV感染的细胞类型特异性和潜伏状态的分子机制，我们还知之甚少。最近，我们描述了一种用于分析HCMV主要立即早期（IE）启动子调控的转基因小鼠模型，并表明在小鼠胚胎发育过程中IE启动子活性位点与人类胎儿先天性HCMV感染的已知靶组织相关（Koedood等人，1995年）。在各种易感染的人体组织中，大脑是HCMV感染可能造成严重破坏的部位。在此，我们使用免疫组织化学双重标记分析来鉴定在几个出生后阶段转基因小鼠大脑中具有HCMV-IE启动子活性的特定细胞类型。IE启动子活性局限于前脑、脑干和小脑中离散位置的一些内皮细胞、室管膜细胞、脉络丛上皮细胞和神经元。具有活性的内皮细胞和神经元在新生小鼠大脑中的比例比成年小鼠大脑中更高。尽管IE启动子在大多数星形胶质细胞中通常是沉默的，但在新皮质刺伤损伤后，反应性星形胶质细胞中会强烈诱导其活性。这些发现支持了一个与HCMV脑炎临床文献一致的模型，即HCMV感染内皮细胞和室管膜细胞所导致的组织损伤和胶质增生会逐渐使相邻的易感染神经元和反应性星形胶质细胞易于感染。这种转基因模型系统应有助于识别在感染易感性和从潜伏状态重新激活方面调节HCMV IE启动子的因素。
