Bid regulates the pathogenesis of neurotropic reovirus.

Danthi P, Pruijssers AJ, Berger AK, Holm GH, Zinkel SS, Dermody TS
PLoS Pathog. 2010 6: e1000980

PMID: 20617182 · PMCID: PMC2895667 · DOI:10.1371/journal.ppat.1000980

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.

MeSH Terms (15)

Animals Apoptosis BH3 Interacting Domain Death Agonist Protein Encephalitis, Viral Fas-Associated Death Domain Protein Fibroblasts Humans L Cells (Cell Line) Mice NF-kappa B Receptors, TNF-Related Apoptosis-Inducing Ligand Reoviridae Reoviridae Infections Signal Transduction Virus Replication

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