title: Crosstalk between the type 1 interferon and nuclear factor kappa B pathways confers resistance to a lethal virus infection.
abstract: 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.
authors.affiliation: Immune Cell Development and Host Defense Program, Research Institute of Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Rubio
authors.forename: Ren-Huan
authors.initials: RH
authors.lastname: Xu
authors.forename: Sanda
authors.initials: S
authors.lastname: Remakus
authors.forename: Tracy E
authors.initials: TE
authors.lastname: Krouse
authors.forename: Mary Ellen
authors.initials: ME
authors.lastname: Truckenmiller
authors.forename: Roshan J
authors.initials: RJ
authors.lastname: Thapa
authors.forename: Siddharth
authors.initials: S
authors.lastname: Balachandran
authors.forename: Antonio
authors.initials: A
authors.lastname: Alcamí
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Norbury
authors.forename: Luis J
authors.initials: LJ
authors.lastname: Sigal
mesh_terms: D000818:Animals; D004481:Ectromelia virus / Q000276:immunology*; D004482:Ectromelia, Infectious / Q000276:immunology*; D007113:Immunity, Innate; D007370:Interferon Type I / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000276:immunology* / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D007370:Interferon Type I; D016328:NF-kappa B