Abstract：
Human cytomegalovirus (HCMV) infection in infants infected in utero can lead to a variety of neurodevelopmental disorders. However, mechanisms underlying altered neurodevelopment in infected infants remain poorly understood. We have previously described a murine model of congenital HCMV infection in which murine CMV (MCMV) spreads hematogenously and establishes a focal infection in all regions of the brain of newborn mice, including the cerebellum. Infection resulted in disruption of cerebellar cortical development characterized by reduced cerebellar size and foliation. This disruption was associated with altered cell cycle progression of the granule cell precursors (GCPs), which are the progenitors that give rise to granule cells (GCs), the most abundant neurons in the cerebellum. In the current study, we have demonstrated that MCMV infection leads to prolonged GCP cell cycle, premature exit from the cell cycle, and reduced numbers of GCs resulting in cerebellar hypoplasia. Treatment with TNF-α neutralizing antibody partially normalized the cell cycle alterations of GCPs and altered cerebellar morphogenesis induced by MCMV infection. Collectively, our results argue that virus-induced inflammation altered the cell cycle of GCPs resulting in a reduced numbers of GCs and cerebellar cortical hypoplasia, thus providing a potential mechanism for altered neurodevelopment in fetuses infected with HCMV.
摘要：
人巨细胞病毒(HCMV)感染在宫内感染的婴儿可导致多种神经发育障碍。然而,感染婴儿神经发育改变的潜在机制仍然知之甚少。我们先前已经描述了先天性HCMV感染的小鼠模型，其中小鼠CMV（MCMV）通过血液传播并在新生小鼠的大脑的所有区域建立局灶性感染，包括小脑.感染导致小脑皮质发育中断，其特征是小脑大小和叶减少。这种破坏与颗粒细胞前体（GCP）的细胞周期进程改变有关，它们是产生颗粒细胞(GC)的祖细胞，小脑中最丰富的神经元。在目前的研究中,我们已经证明MCMV感染导致GCP细胞周期延长，过早退出细胞周期,GCs数量减少导致小脑发育不全。用TNF-α中和抗体治疗可使MCMV感染诱导的GCP细胞周期改变和小脑形态发生改变部分正常化。总的来说，我们的结果表明，病毒诱导的炎症改变了GCP的细胞周期，导致GCs数量减少和小脑皮质发育不全，从而为HCMV感染胎儿的神经发育改变提供了潜在的机制。
