title: NF-kappaB-mediated inhibition of apoptosis is required for encephalomyocarditis virus virulence: a mechanism of resistance in p50 knockout mice.
abstract: Apoptosis is a central host defense mechanism to eliminate virus-infected cells. Activation of NF-kappaB suppresses apoptosis following some types of stimulation in vitro. To test the physiological importance of this pathway in vivo, we studied murine encephalomyocarditis virus (EMCV) infection in mice and cell lines defective in NF-kappaB1 (p50) signaling. As previously reported, we find that all p50 knockout (p50 -/-) mice survive an EMCV infection that readily kills normal mice. By introducing the p50 mutation into interferon (IFN) type I receptor knockout (IFNRI -/-) mice, we find that this resistance is not mediated by IFN-beta as previously thought. While no IFNRI -/- mice survive, the double-knockout mice survive 60% of the time. The survival is tightly linked to the animals' ability to clear the virus from the heart in vivo. Using murine embryonic fibroblasts (MEF) derived from wild-type, p50 -/-, and p65 -/- embryos, we found that NF-kappaB is not required for the replication cycle of EMCV. However, during these experiments we observed that p50 -/- and p65 -/- MEF infected with EMCV undergo enhanced, premature cytotoxicity. Upon examination of this cell death, we found that EMCV infection induced both plasma membrane and nuclear changes typical of apoptosis in all cell lines. These apoptotic processes occurred in an accelerated and pronounced way in the NF-kappaB-defective cells, as soon as 6 h after infection, when virus is beginning to be released. Previously, only the RelA (p65) subunit of NF-kappaB has been shown to play a role in suppressing apoptosis. In our studies, we find that p50 is equally important in suppressing apoptosis during EMCV infection. Additionally, we show that suppression of apoptosis by NF-kappaB1 is required for EMCV virulence in vivo. The attenuation in p50 -/- mice can be explained by rapid apoptosis of infected cells which allows host phagocytes to clear infected cells before the viral burst leading to a reduction of the viral burden and survival of the mice.
authors.affiliation: Laboratory of Genetics, The Salk Institute, San Diego, California 92186-5800, USA.
authors.forename: E M
authors.initials: EM
authors.lastname: Schwarz
authors.forename: C
authors.initials: C
authors.lastname: Badorff
authors.forename: T S
authors.initials: TS
authors.lastname: Hiura
authors.forename: R
authors.initials: R
authors.lastname: Wessely
authors.forename: A
authors.initials: A
authors.lastname: Badorff
authors.forename: I M
authors.initials: IM
authors.lastname: Verma
authors.forename: K U
authors.initials: KU
authors.lastname: Knowlton
mesh_terms: D000818:Animals; D017209:Apoptosis; D018188:Cardiovirus Infections / Q000276:immunology*; D004686:Encephalomyocarditis virus / Q000472:pathogenicity*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000502:physiology*; D017471:Receptors, Interferon / Q000502:physiology*; D014774:Virulence; D014779:Virus Replication
chemical_list: D016328:NF-kappa B; D017471:Receptors, Interferon