I. Kosugi et al., MURINE CYTOMEGALOVIRUS INDUCES APOPTOSIS IN NONINFECTED CELLS OF THE DEVELOPING MOUSE-BRAIN AND BLOCKS APOPTOSIS IN PRIMARY NEURONAL CULTURE, Acta Neuropathologica, 96(3), 1998, pp. 239-247
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.