BCL-2 PROTECTS MICE AGAINST FATAL ALPHAVIRUS ENCEPHALITIS

Virus-induced apoptosis has been well characterized in vitro, but the role of apoptosis in viral pathogenesis is not well understood. The su icide of a cell in response to viral infection is postulated to be an important host defense for the organism, leading to a reduction in its total viral burden. However, virus-induced death of nonregenerating c ells in the central nervous system may be detrimental to the host. The refore, to investigate the role of apoptosis in the pathogenesis of fa tal encephalitis, we constructed a recombinant alphavirus chimera that expresses the antiapoptotic gene, bcl-2, in virally infected neural c ells. Infection of neonatal mice with the alphavirus chimera expressin g human bcl-2 [Sindbis virus (SIN)/bcl-2] resulted in a significantly lower mortality rate (7.5%) as compared with infection with control ch imeric viruses containing a chloramphenicol acetyltransferase (CAT) re porter gene (SIN/CAT) (78.1%) or bcl-2 containing a premature stop cod on (SIN/bcl-2stop) (72.1%) (P < 0.001). Viral titers were reduced 5-fo ld 1 day after infection and 10-fold 6 days after infection in the bra ins of SIN/bcl-2-infected mice as compared to SIN/CAT or SIN/bcl-2stop -infected mice. In Situ end labeling to detect apoptotic nuclei demons trated a reduction in the number of foci of apoptotic cells in the bra ins of mice infected with SIN/bcl-2 as compared with SIN/bcl-2stop. Th e reduction in apoptosis was associated with a reduction in the number of foci of cells expressing alphavirus RNA. Thus, the antiapoptotic g ene, bcl-2, suppresses viral replication and protects against a lethal viral disease, suggesting an interaction between cellular genetic con trol of viral replication and cell death.