into a mainstream tool for the assessment of the status of the human immune system. Bid Regulates the Pathogenesis of Neurotropic Reovirus Reovirus infection leads to apoptosis in both cultured cells and the murine central nervous system (CNS). NF-κB-driven transcription of proapoptotic cellular genes is required for the effector phase of the apoptotic response. Although both extrinsic death-receptor signaling pathways and intrinsic pathways involving mitochondrial injury are implicated in reovirus-induced apoptosis, mechanisms by which either of these pathways are activated and their relationship to NF-κB signaling following reovirus infection are unknown. The proapoptotic Bcl-2 family member, Bid, is activated by proteolytic cleavage following reovirus infection. To understand how reovirus integrates host signaling circuits to induce apoptosis, we examined proapoptotic signaling following infection of Bid-deficient cells. Although reovirus growth was not affected by the absence of Bid, cells lacking Bid failed to undergo apoptosis. Furthermore, we found that NF-κB activation is required for Bid cleavage and subsequent proapoptotic signaling. To examine the functional significance of Bid-dependent apoptosis in reovirus disease, we monitored fatal encephalitis caused by reovirus in the presence and absence of Bid. Survival of Bid-deficient mice was significantly enhanced in comparison to wild-type mice following either peroral or intracranial inoculation of reovirus. Decreased reovirus virulence in Bid-null mice was accompanied by a reduction in viral yield. These findings define a role for NF-κB-dependent cleavage of Bid in the cell death program initiated by viral infection and link Bid to viral virulence. Tissue injury in response to infections by many viruses occurs as a consequence of apoptosis. Multiple studies using animal models of viral disease demonstrate a correlation between apoptotic potential and disease severity [1, 2, 3, 4] . These observations highlight proapoptotic signaling following virus infection as an attractive target for antiviral therapy. However, despite its central importance in viral pathogenesis, gaps in knowledge about the identity of death signaling pathways that modulate virus-induced apoptosis in vivo, along with an incomplete understanding of how these signaling cascades are activated during virus infection, have hampered the deployment of this strategy for treatment of viral disease.