Organ-specific roles for transcription factor NF-κB in reovirus-induced apoptosis and disease

• Published in: The Journal of clinical investigation 2005-09, Vol.115 (9), p.2341-2350
• Main Authors: O’Donnell, Sean M., Hansberger, Mark W., Connolly, Jodi L., Chappell, James D., Watson, Melissa J., Pierce, Janene M., Wetzel, J. Denise, Han, Wei, Barton, Erik S., Forrest, J. Craig, Valyi-Nagy, Tibor, Yull, Fiona E., Blackwell, Timothy S., Rottman, Jeffrey N., Sherry, Barbara, Dermody, Terence S.
• Format: Article
• Language: English
• ISSN: 0021-9738
• DOI: 10.1172/JCI22428

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-κB complexes containing p50 and p65/RelA subunits. To explore the in vivo role of NF-κB 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-β 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-β substantially diminished reovirus replication and apoptosis, which suggests that IFN-β induction by NF-κB protects against reovirus-induced myocarditis. These findings reveal an organ-specific role for NF-κB in the regulation of reovirus-induced apoptosis, which modulates encephalitis and myocarditis associated with reovirus infection.