Organ-specific roles for transcription factor NF-kappaB in reovirus-induced apoptosis and disease.
O'Donnell SM,
Hansberger MW,
Connolly JL,
Chappell JD,
Watson MJ,
Pierce JM,
Wetzel JD,
Han W,
Barton ES,
Forrest JC,
Valyi-Nagy T,
Yull FE,
Blackwell TS,
Rottman JN,
Sherry B,
Dermody TS.
Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
Reovirus induces apoptosis in cultured cells and in vivo. In cell culture models, apoptosis is contingent upon a mechanism involving reovirus-induced activation of transcription factor NF-kappaB complexes containing p50 and p65/RelA subunits. To explore the in vivo role of NF-kappaB in this process, we tested the capacity of reovirus to induce apoptosis in mice lacking a functional nfkb1/p50 gene. The genetic defect had no apparent effect on reovirus replication in the intestine or dissemination to secondary sites of infection. In comparison to what was observed in wild-type controls, apoptosis was significantly diminished in the CNS of p50-null mice following reovirus infection. In sharp contrast, the loss of p50 was associated with massive reovirus-induced apoptosis and uncontrolled reovirus replication in the heart. Levels of IFN-beta mRNA were markedly increased in the hearts of wild-type animals but not p50-null animals infected with reovirus. Treatment of p50-null mice with IFN-beta substantially diminished reovirus replication and apoptosis, which suggests that IFN-beta induction by NF-kappaB protects against reovirus-induced myocarditis. These findings reveal an organ-specific role for NF-kappaB in the regulation of reovirus-induced apoptosis, which modulates encephalitis and myocarditis associated with reovirus infection.
PMID: 16100570 [PubMed - indexed for MEDLINE]
PMCID: PMC1184036