Cytomegalovirus infection of the central nervous system stem cells from mouse embryo: A model for developmental brain disorders induced by cytomegalovirus

Cytomegalovirus (CMV) is the most frequent infectious cause of developmenta l disorders of the central nervous system (CNS) in humans. Infection of the CNS stem cells seems to be primarily responsible for the generation of the brain abnormalities. In this study, we evaluated the infectivity of murine CMV (MCMV) in epidermal growth factor (EGF)-responsive CNS stem cells prep ared from fetal mouse brains, and studied the effect of infection on growth and differentiation of the stem cells. The CNS stem cells were permissive for MCMV infection, although MCMV replication was slower than in mouse embr yonic fibroblasts. MCMV infection inhibited the growth and DNA replication of the stem cells. A clonogenic assay revealed that MCMV infection suppress ed generation of colonies from single stem cells. When uninfected stem cell s were induced to differentiate, a decrease in expression of the primitive neuroepidermal marker nestin was observed by immunocytochemistry and flow c ytometry, whereas expression of neurofilament and glial fibrillary acidic p rotein (GFAP) were induced, in virus-infected CNS stem cells, nestin expres sion was retained, whereas the expression of neurofilament was more severel y inhibited than that of GFAP in these cells. Two-color flow cytometry show ed that differentiated glial precursor cells were preferentially susceptibl e to MCMV infection. MCMV-infected and uninfected CNS stem cells were trans planted into the neonatal rat brains. The reduced number of infected stem c ells were engulfed into the subventricular zone and expressed GFAP, but did not migrate further, in contrast to the uninfected stem cells. These resul ts suggest that suppression of the growth of the CNS stem cells and inhibit ion of the neuronal differentiation by CMV infection may be primary causes of disorders of brain development in congenital CMV infection.