NF-κB-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-κB 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-κB1 (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-β 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-κB 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-κB-defective cells, as soon as 6 h after infection, when virus is beginning to be released. Previously, only the RelA (p65) subunit of NF-κB 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-κB1 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.

Encephalomyocarditis Virus 3C Protease Relieves TRAF Family Member-associated NF-κB Activator (TANK) Inhibitory Effect on TRAF6-mediated NF-κB Signaling through Cleavage of TANK

“…In this study, we found that TANK is a novel substrate of EMCV 3C, which is cleaved at Gln-291 to yield an N-terminal (47). The survival rate of p50 Ϫ/Ϫ mice is higher than that of p50 ϩ/ϩ mice after EMCV infection, which is tightly linked to the animals' ability to clear the virus from the heart in vivo (48). Kawagoe et al (37) also demonstrated that macrophages and B cells isolated from tank Ϫ/Ϫ mice have a greater potential to activate canonical NF-B signaling in response to the stimulation of TLRs and B cell receptors.…”

Porcine arterivirus activates the NF-κB pathway through IκB degradation

“…The NF-nB pathway can also be activated directly by viruses. Viruses including HIV, herpesviruses, hepatitis C virus, encephalomyocarditis virus, reovirus, dengue virus, West Nile virus, and herpes simplex virus have evolved strategies to activate NF-nB to exploit NF-nB for optimized replication, or to control host cell proliferation and survival to maximize viral progeny production (Connolly et al, 2000;Goodkin et al, 2003;Jan et al, 2000;Santoro et al, 2003;Schwarz et al, 1998;Waris et al, 2003). Despite the importance of the NF-nB pathway in immune response, it has not been determined if PRRSV or other arteriviruses modulate this pathway.…”

Reovirus Binding to Cell Surface Sialic Acid Potentiates Virus-Induced Apoptosis

“…Many viruses are capable of inducing the genetically programmed death pathway that leads to apoptosis of infected cells (36,50,52). In some cases, apoptosis triggered by virus infection may serve as a host defense mechanism to limit viral replication (48). In other instances, induction of apoptosis may enhance viral infection by facilitating virus spread or allowing the virus to evade host inflammatory or immune responses (10,36,52).…”