Infection of fetal neural tissue by guinea pig cytomegalovirus: Association of cell types infected and neuropathogenesis.

Abstract

The specific relationship between human congenital cytomegalovirus infection, neuropathological changes such as microcephaly and calcifications and neurologic dysfunction such as mental retardation is not clear. Of special interest is how a limited number of infected cells leads to global effects such as microcephaly and mental retardation. Guinea pig cytomegalovirus (GPCMV) was used to investigate which cell types in the guinea pig fetal nervous system are infectable and the relationship between infection and associated problems. Monoclonal antibodies with specific reactivity against GPCMV proteins were made. One was found to label infected cells in vivo and in vitro and was characterized as identifying a late structural protein of GPCMV. In cells infected by GPCMV, a comparison of viral protein production was undertaken using the newly created monoclonal antibody against GPCMV and antisera against multiple GPCMV proteins. GPCMV infected cells were identified using the monoclonal antibody and anti-GPCMV antisera. The specific fetal brain cell types infected by GPCMV were identified in vitro and in vivo by anatomical localization and immunocytochemical labelling with cell specific antibodies directed against neurons, astrocytes, progenitor cells, macrophages, and endothelial cells. In fetal brain cells, fewer infected cells expressed the late structural protein recognized by the monoclonal antibody than were labelled with the polyclonal antisera. This difference was not seen in infected salivary gland or fibroblasts. In vivo infection was determined to be localized primarily to areas adjacent to the lateral ventricles. Endothelial cells and ependymal cells were determined to be infected in vivo by GPCMV. Macrophages and progenitor cells were found to be infected by GPCMV in vitro. These studies suggest that not only are certain cell types infected but the pattern of viral protein expression may differ between cell types and perhaps developmental stage. Infection of endothelial, ependymal and progenitor cells may destroy the substrate necessary for normal brain development and lead to the developmental derangements of the fetal brain known to be associated with human congenital cytomegalovirus infection.