MURINE CYTOMEGALOVIRUS INDUCES APOPTOSIS IN NONINFECTED CELLS OF THE DEVELOPING MOUSE-BRAIN AND BLOCKS APOPTOSIS IN PRIMARY NEURONAL CULTURE

Cytomegalovirus (CMV) is the most common cause of congenital infection , resulting in birth defects such as microcephaly. In this study, we f ound that apoptosis is induced in the developing mouse brain infected with murine cytomegalovirus (MCMV) in an association with neuronal cel l loss. With the combination of the terminal deoxynucleotidyl transfer ase-mediated dUTP nick end labeling (TUNEL) technique and immunohistoc hemical staining, 3.8% of the TUNEL-positive cells were double-stained with the antibody to neuron-specific enolase, while none of the TUNEL -positive cells were stained with antibodies to the immediate early an d early viral antigens of MCMV. Furthermore, distribution pattern of t he TUNEL-positive cells was different from that of viral DNA-positive cells detected by the in situ DNA-DNA hybridization. More than 30% of the TUNEL-positive cells were double-stained with the F4/80 antibody s pecific for microglia/macrophages, which were sometimes swollen, presu mably the consequence of engulfment of the neuronal apoptotic cells. I n the primary neuronal cultures, MCMV infection inhibited the inductio n of apoptosis either by serum deprivation or by glutamate treatment. It was also confirmed by the double-staining method that apoptosis was not induced in the viral-infected neuronal cultures. These results su ggest that MCMV infection induces apoptosis in non-infected neuronal c ells, presumably by indirect mechanisms, and that apoptotic cells are engulfed by microglia/macrophages. The induction and blocking of neuro nal apoptosis by viral infection may be important for morphological an d functional brain disorders in the congenital CMV infection.