Abstract
BackgroundCongenital cytomegalovirus (CMV) brain infection causes serious neuro-developmental sequelae including: mental retardation, cerebral palsy, and sensorineural hearing loss. But, the mechanisms of injury and pathogenesis to the fetal brain are not completely understood. The present study addresses potential pathogenic mechanisms by which this virus injures the CNS using a neonatal mouse model that mirrors congenital brain infection. This investigation focused on, analysis of cell types infected with mouse cytomegalovirus (MCMV) and the pattern of injury to the developing brain.Methodology/Principal FindingsWe used our MCMV infection model and a multi-color flow cytometry approach to quantify the effect of viral infection on the developing brain, identifying specific target cells and the consequent effect on neurogenesis. In this study, we show that neural stem cells (NSCs) and neuronal precursor cells are the principal target cells for MCMV in the developing brain. In addition, viral infection was demonstrated to cause a loss of NSCs expressing CD133 and nestin. We also showed that infection of neonates leads to subsequent abnormal brain development as indicated by loss of CD24(hi) cells that incorporated BrdU. This neonatal brain infection was also associated with altered expression of Oct4, a multipotency marker; as well as down regulation of the neurotrophins BDNF and NT3, which are essential to regulate the birth and differentiation of neurons during normal brain development. Finally, we report decreased expression of doublecortin, a marker to identify young neurons, following viral brain infection.ConclusionsMCMV brain infection of newborn mice causes significant loss of NSCs, decreased proliferation of neuronal precursor cells, and marked loss of young neurons.
Highlights
Cytomegalovirus (CMV) is the most common infectious cause of developmental disorders of the central nervous system (CNS) in humans and the predominant cause of developmental neurological disabilities in the United States [1]
There is an abundance of NSCs in the fetal brain, in this study we will use the term neural stem cells to refer to all classes of immature and proliferating cells that reacted with CD133 and nestin
We show that infection of the developing brain, which is rich in NSCs, results in reduced expression of doublecortin (DCX), a marker that identifies young/immature neurons, while the glial precursor and mature astrocyte marker, glial acidic fibrillary protein (GFAP) expression remained unaltered
Summary
Cytomegalovirus (CMV) is the most common infectious cause of developmental disorders of the central nervous system (CNS) in humans and the predominant cause of developmental neurological disabilities in the United States [1]. There is an abundance of NSCs in the fetal brain, in this study we will use the term neural stem cells to refer to all classes of immature and proliferating cells that reacted with CD133 and nestin The susceptibility of these cells to viral infection could provide insights into the neuropathogenesis of CMV during brain development [6]. The present study addresses potential pathogenic mechanisms by which this virus injures the CNS using a neonatal mouse model that mirrors congenital brain infection. This investigation focused on, analysis of cell types infected with mouse cytomegalovirus (MCMV) and the pattern of injury to the developing brain
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