Laboratory of Immuno-hematology, Department of Genetic and Laboratory Medicine, Geneva University Hospital, University of Geneva, Geneva, Switzerland; Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland; BioTalentum Ltd, Gödöllö 2100, Hungary.
Biomaterials. 2015;53:296-308. doi: 10.1016/j.biomaterials.2015.02.094. Epub 2015 Mar 17.
Human cytomegalovirus (HCMV) is the most common cause of congenital infection of the central nervous system (CNS). To overcome the limited access to human neural tissue and stringent species specificity of HCMV, we used engineered neural tissues to: (i) provide a technical advance to mimick features of HCMV infection in a human neural fetal tissue in vitro and (ii) characterize the molecular and cellular phenomenon following HCMV infection in this tissue. Herein, we infected hESC-derived engineered neural tissues (ENTs) whose organization resembles fetal brain. Transcriptome analysis of ENTs demonstrated that HCMV infection displayed features of the infection with the expression of genes involved in lipid metabolism, growth and development, as well as stress and host-response in a time-dependent manner. Immunohistochemical analysis demonstrated that HCMV did not firstly infect neural tubes (i.e. radially organized, proliferating stem cell niches), but rather an adjacent side population of post-mitotic cells expressing nestin, doublecortin, Sox1, musashi and vimentin markers. Importantly, we observe the same tropism in naturally HCMV-infected fetal brain specimens. To the best of our knowledge this system represents the first human brain-like tissue able to provide a more physiologically model for studying HCMV infection.
人类巨细胞病毒（HCMV）是引起中枢神经系统（CNS）先天性感染的最常见原因。为了克服获取人类神经组织的局限性和 HCMV 的严格种属特异性，我们使用工程化神经组织来：（i）提供技术进步，以模拟人类神经原代组织中 HCMV 感染的特征；（ii）描述该组织中 HCMV 感染后的分子和细胞现象。在此，我们感染了 hESC 衍生的工程化神经组织（ENT），其组织类似于胎儿大脑。ENT 的转录组分析表明，HCMV 感染表现出与感染相关的特征，其基因表达涉及脂质代谢、生长发育以及应激和宿主反应，具有时间依赖性。免疫组织化学分析表明，HCMV 并非首先感染神经管（即放射状组织、增殖性干细胞龛），而是相邻的具有巢蛋白、双皮质素、Sox1、玛莎西和波形蛋白标志物的有丝分裂后细胞亚群。重要的是，我们在自然感染 HCMV 的胎儿脑组织标本中观察到相同的嗜性。据我们所知，该系统代表了第一个能够提供更接近生理模型以研究 HCMV 感染的类人脑组织。
