Viruses injure host tissues by activating signaling pathways that trigger cell death by a process called apoptosis. Hence, blockade of apoptosis may serve as a useful strategy to dampen the severity of viral disease. However, deployment of such a strategy requires identification of host signaling networks that control cell death and a detailed molecular blueprint of how these pathways are activated by a virus. In this study, we used mammalian reovirus, an important experimental model for studies of viral encephalitis, to elucidate how cell death pathways are activated following viral infection and whether these signaling cascades influence the capacity of a virus to produce lethal CNS disease. We found that Bid, a host regulator of cell death, influences apoptosis induction by reovirus. Moreover, Bid is required for efficient reovirus replication in the CNS and modulates reovirus neurological disease. These findings highlight Bid as a critical regulator of viral pathogenesis and illuminate a potential new target for development of antiviral therapeutics. (A) L929 cells were adsorbed with PBS (mock) or reovirus T3D at an MOI of 100 PFU/cell. Following incubation at 37uC for the indicated intervals, whole cell extracts were prepared, resolved by SDS-PAGE, and immunoblotted using antisera specific for Bid, actin, or procasapse-9. (B) L929 cells were adsorbed with reovirus T3D at an MOI of 100 PFU/cell. Following incubation at 37uC for the indicated intervals in the presence of 0 or 10 mM of Z-IETD-FMK, whole cell extracts were prepared, resolved by SDS-PAGE, and immunoblotted using antisera specific for Bid, actin, or procasapse-9. Protein bands are indicated on the right. A non-specific band is indicated by an asterisk (*). doi:10.1371/journal.ppat.1000980.g001 levels of procaspase-9 as a surrogate for the formation of the caspase-9-containing apoptosome ( Figure 1A ). In a time frame consistent with cleavage-induced generation of tBid, we observed a decrease in procaspase-9 levels in reovirus-infected cells. These findings suggest that following reovirus infection of murine fibroblasts, Bid serves to activate the mitochondrial apoptotic pathway.