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Journal of Neuroscience, Vol 16, 2275-2282, Copyright © 1996 by Society for Neuroscience
Brain cell type specificity and gliosis-induced activation of the human cytomegalovirus immediate-early promoter in transgenic mice
JM Fritschy, S Brandner, A Aguzzi, M Koedood, B Luscher and PJ Mitchell
Institutes of Molecular Biology, University of Zurich, CH-8057 Zurich, Switzerland.
Human cytomegalovirus (HCMV) can cause debilitating, sometimes fatal,
opportunistic infections in congenitally infected infants and in
immunodeficient individuals such as patients with the acquired
immunodeficiency syndrome (AIDS). Molecular mechanisms that determine cell
type specificity of HCMV infection and latency are poorly understood. We
recently described a transgenic mouse model for analysis of HCMV major
immediate-early (IE) promoter regulation and showed that sites of IE
promoter activity during murine embryogenesis correlate with known target
tissues of congenital HCMV infection in human fetuses (Koedood et al.,
1995). Among various permissive human tissues, the brain is a site where
HCMV infections can be devastating. Here, we have used immunohistochemical
double-labeling analysis to identify specific cell types with HCMV-IE
promoter activity in brains of transgenic mice at several postnatal stages.
IE promoter activity was restricted to some endothelial cells, ependymal
cells, choroid plexus epithelia, and neurons at discrete locations in the
forebrain, brainstem, and cerebellum. Endothelial cells and neurons with
activity were proportionately more abundant in neonatal than in adult
brains. Although the IE promoter was normally silent in most astrocytes,
activity was strongly induced in reactive astrocytes in response to a
neocortical stab lesion. The findings support a model, consistent with
clinical literature on HCMV encephalitis, whereby tissue damage and gliosis
caused by HCMV infection of endothelial and ependymal cells progressively
renders adjacent permissive neurons and reactive astrocytes accessible to
infection. This transgenic model system should facilitate identification of
factors that regulate the HCMV IE promoter with regard to infection
permissivity and reactivation from latency.
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