Encephalitis induced by reovirus serotype 3 (T3) strains results from the 
apoptotic death of infected neurons. Extrinsic apoptotic signaling is activated 
in reovirus-infected neurons in vitro and in vivo, but the role of intrinsic 
apoptosis signaling during encephalitis is largely unknown. Bax plays a key role 
in intrinsic apoptotic signaling in neurons by allowing the release of 
mitochondrial cytochrome c. We found Bax activation and cytochrome c release in 
neurons following infection of neonatal mice with T3 reoviruses. Bax(-/-) mice 
infected with T3 Abney (T3A) have reduced central nervous system (CNS) tissue 
injury and decreased apoptosis, despite viral replication that is similar to 
that in wild-type (WT) Bax(+/+) mice. In contrast, in the heart, T3A-infected 
Bax(-/-) mice have viral growth, caspase activation, and injury comparable to 
those in WT mice, indicating that the role of Bax in pathogenesis is organ 
specific. Nonmyocarditic T3 Dearing (T3D)-infected Bax(-/-) mice had delayed 
disease and enhanced survival compared to WT mice. T3D-infected Bax(-/-) mice 
had significantly lower viral titers and levels of activated caspase 3 in the 
brain despite unaffected transneuronal spread of virus. Cytochrome c and Smac 
release occurred in some reovirus-infected neurons in the absence of Bax; 
however, this was clearly reduced compared to levels seen in Bax(+/+) wild-type 
mice, indicating that Bax is necessary for efficient activation of proapoptotic 
mitochondrial signaling in infected neurons. Our studies suggest that Bax is 
important for reovirus growth and pathogenesis in neurons and that the intrinsic 
pathway of apoptosis, mediated by Bax, is important for full expression of 
disease, CNS tissue injury, apoptosis, and viral growth in the CNS of 
reovirus-infected mice.