Crosstalk between the Type 1 Interferon and Nuclear Factor Kappa B Pathways Confers Resistance to a Lethal Virus Infection

Nuclear factor kappa B (NF-κB) and type 1 interferon (T1-IFN) signaling are innate immune mechanisms activated upon viral infection. However, the role of NF-κB and its interplay with T1-IFN in antiviral immunity is poorly understood. We show that NF-κB is essential for resistance to ectromelia virus...

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Bibliographic Details
Published in:Cell host & microbe 2013-06, Vol.13 (6), p.701-710
Main Authors: Rubio, Daniel, Xu, Ren-Huan, Remakus, Sanda, Krouse, Tracy E., Truckenmiller, Mary Ellen, Thapa, Roshan J., Balachandran, Siddharth, Alcamí, Antonio, Norbury, Christopher C., Sigal, Luis J.
Format: Article
Language:English
Subjects:
Animals
Ectromelia virus - immunology
Ectromelia, Infectious - immunology
Immunity, Innate
Interferon Type I - immunology
Interferon Type I - metabolism
Mice
NF-kappa B - immunology
NF-kappa B - metabolism
Signal Transduction
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Summary:Nuclear factor kappa B (NF-κB) and type 1 interferon (T1-IFN) signaling are innate immune mechanisms activated upon viral infection. However, the role of NF-κB and its interplay with T1-IFN in antiviral immunity is poorly understood. We show that NF-κB is essential for resistance to ectromelia virus (ECTV), a mouse orthopoxvirus related to the virus causing human smallpox. Additionally, an ECTV mutant lacking an NF-κB inhibitor activates NF-κB more effectively in vivo, resulting in increased proinflammatory molecule transcription in uninfected cells and organs and decreased viral replication. Unexpectedly, NF-κB activation compensates for genetic defects in the T1-IFN pathway, such as a deficiency in the IRF7 transcription factor, resulting in virus control. Thus, overlap between the T1-IFN and NF-κB pathways allows the host to overcome genetic or pathogen-induced deficiencies in T1-IFN and survive an otherwise lethal poxvirus infection. These findings may also explain why some pathogens target both pathways to cause disease. •NF-κB signaling is essential for resistance to an acute lethal poxvirus infection•In vivo NF-κB activation in infected cells induces cytokines in uninfected cells•Enhanced NF-κB activation overcomes suboptimal type 1 interferon (T1-IFN) production•Viral infection induces interferon-stimulated genes independently of T1-IFN or NF-κB
ISSN:1931-3128
1934-6069
DOI:10.1016/j.chom.2013.04.015