BRAIN-CELL TYPE SPECIFICITY AND GLIOSIS-INDUCED ACTIVATION OF THE HUMAN CYTOMEGALOVIRUS IMMEDIATE-EARLY PROMOTER IN TRANSGENIC MICE

Human cytomegalovirus (HCMV) can cause debilitating, sometimes fatal, opportunistic infections in congenitally infected infants and in immun odeficient individuals such as patients with the acquired immunodefici ency syndrome (AIDS). Molecular mechanisms that determine cell type sp ecificity of HCMV infection and latency are poorly understood. We rece ntly described a transgenic mouse model for analysis of HCMV major imm ediate-early (IE) promoter regulation and showed that sites of IE prom oter 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 wh ere HCMV infections can be devastating. Here, we have used immunohisto chemical double-labeling analysis to identify specific cell types with HCMV-IE promoter activity in brains of transgenic mice at several pos tnatal stages. IE promoter activity was restricted to some endothelial cells, ependymal cells, choroid plexus epithelia, and neurons at disc rete locations in the forebrain, brainstem, and cerebellum. Endothelia l cells and neurons with activity were proportionately more abundant i n 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 supp ort a model, consistent with clinical literature on HCMV encephalitis, whereby tissue damage and gliosis caused by HCMV infection of endothe lial and ependymal cells progressively renders adjacent permissive neu rons 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 reacti vation from latency.