PDF(Pubmed)
Abstract：
Human cytomegalovirus (CMV) infection is the leading non-genetic aetiology of congenital malformation in developed countries, causing significant fetal neurological injury. This study investigated potential CMV pathogenetic mechanisms of fetal neural malformation using in vitro human cerebral organoids. Cerebral organoids were permissive to CMV replication, and infection dysregulated cellular pluripotency and differentiation pathways. Aberrant expression of dual-specificity tyrosine phosphorylation-regulated kinases (DYRK), sonic hedgehog (SHH), pluripotency, neurodegeneration, axon guidance, hippo signalling and dopaminergic synapse pathways were observed in CMV-infected organoids using immunofluorescence and RNA-sequencing. Infection with CMV resulted in dysregulation of 236 Autism Spectrum Disorder (ASD)-related genes (p = 1.57E-05) and pathways. This notable observation suggests potential links between congenital CMV infection and ASD. Using DisGeNET databases, 103 diseases related to neural malformation or mental disorders were enriched in CMV-infected organoids. Cytomegalovirus infection-related dysregulation of key cerebral cellular pathways potentially provides important, modifiable pathogenetic mechanisms for congenital CMV-induced neural malformation and ASD.
摘要：
人类巨细胞病毒（CMV）感染是发达国家先天性畸形的主要非遗传病因，造成严重的胎儿神经损伤。这项研究使用体外人脑类器官研究了胎儿神经畸形的潜在CMV发病机制。脑类器官允许CMV复制，和感染失调的细胞多能性和分化途径。双特异性酪氨酸磷酸化调节激酶（DYRK）的异常表达，索尼克刺猬（SHH），多能性,神经变性,轴突引导,使用免疫荧光和RNA测序在CMV感染的类器官中观察到河马信号和多巴胺能突触途径。CMV感染导致236个自闭症谱系障碍（ASD）相关基因（p=1.57E-05）和途径的失调。这一值得注意的观察表明先天性CMV感染与ASD之间存在潜在联系。使用DisGeNET数据库，在CMV感染的类器官中富集了103种与神经畸形或精神障碍相关的疾病。巨细胞病毒感染相关的关键脑细胞通路的失调可能提供重要的,先天性CMV诱导的神经畸形和ASD的可改变的致病机制。
