Organ-specific roles for transcription factor NF-kappaB in reovirus-induced apoptosis and disease.
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.
O'Donnell
Sean M
SM
Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
Hansberger
Mark W
MW
Connolly
Jodi L
JL
Chappell
James D
JD
Watson
Melissa J
MJ
Pierce
Janene M
JM
Wetzel
J Denise
JD
Han
Wei
W
Barton
Erik S
ES
Forrest
J Craig
JC
Valyi-Nagy
Tibor
T
Yull
Fiona E
FE
Blackwell
Timothy S
TS
Rottman
Jeffrey N
JN
Sherry
Barbara
B
Dermody
Terence S
TS
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000502:physiology*; D001921:Brain / Q000166:cytology / Q000378:metabolism / Q000821:virology; D002460:Cell Line; D006321:Heart / Q000821:virology; D020287:In Situ Nick-End Labeling; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000166:cytology / Q000821:virology; D051379:Mice; D018345:Mice, Knockout; D009205:Myocarditis / Q000473:pathology / Q000821:virology; D009206:Myocardium / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D052002:NF-kappa B p50 Subunit / Q000235:genetics / Q000378:metabolism*; D012087:Reoviridae / Q000235:genetics / Q000502:physiology*; D012088:Reoviridae Infections / Q000378:metabolism / Q000473:pathology; D014779:Virus Replication
D052002:NF-kappa B p50 Subunit; D016899:Interferon-beta