Bid regulates the pathogenesis of neurotropic reovirus

Reovirus infection leads to apoptosis in both cultured cells and the murine central nervous system (cns). nf-kb-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 reovirusinduced 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 biddeficient 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. © 2010 danthi et al.