Bid regulates the pathogenesis of neurotropic reovirus.
Reovirus infection leads to apoptosis in both cultured cells and the murine central nervous system (CNS). NF-kappaB-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-kappaB 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-kappaB 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-kappaB-dependent cleavage of Bid in the cell death program initiated by viral infection and link Bid to viral virulence.
Danthi
Pranav
P
Department of Biology, Indiana University, Bloomington, Indiana, United States of America. pdanthi@indiana.edu
Pruijssers
Andrea J
AJ
Berger
Angela K
AK
Holm
Geoffrey H
GH
Zinkel
Sandra S
SS
Dermody
Terence S
TS
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D051023:BH3 Interacting Domain Death Agonist Protein / Q000172:deficiency / Q000502:physiology*; D018792:Encephalitis, Viral / Q000209:etiology*; D053200:Fas-Associated Death Domain Protein / Q000502:physiology; D005347:Fibroblasts / Q000821:virology; D006801:Humans; D007739:L Cells; D051379:Mice; D016328:NF-kappa B / Q000502:physiology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000502:physiology; D012087:Reoviridae / Q000472:pathogenicity*; D012088:Reoviridae Infections / Q000821:virology*; D015398:Signal Transduction / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
D051023:BH3 Interacting Domain Death Agonist Protein; C494815:Bid protein, mouse; D053200:Fas-Associated Death Domain Protein; D016328:NF-kappa B; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand