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

• Published in: The Journal of clinical investigation Vol. 115; no. 9; pp. 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: Journal Article
• Language: English
• Published: United States 01.09.2005
• Subjects: Animals; Animals, Newborn; Apoptosis - physiology; Brain - cytology; Brain - metabolism; Brain - virology; Cell Line; Heart - virology; In Situ Nick-End Labeling; Interferon-beta - genetics; Interferon-beta - metabolism; Intestines - cytology; Intestines - metabolism; Intestines - virology; Mice; Mice, Knockout; Myocarditis - pathology; Myocarditis - virology; Myocardium - cytology; Myocardium - metabolism; Myocardium - pathology; NF-kappa B p50 Subunit - genetics; NF-kappa B p50 Subunit - metabolism; Reoviridae - genetics; Reoviridae - physiology; Reoviridae Infections - metabolism; Reoviridae Infections - pathology; Virus Replication
• ISSN: 0021-9738

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.