title: Sequential Activation of Two Pathogen-Sensing Pathways Required for Type I Interferon Expression and Resistance to an Acute DNA Virus Infection.
abstract: Toll-like receptor 9 (TLR9), its adaptor MyD88, the downstream transcription factor interferon regulatory factor 7 (IRF7), and type I interferons (IFN-I) are all required for resistance to infection with ectromelia virus (ECTV). However, it is not known how or in which cells these effectors function to promote survival. Here, we showed that after infection with ECTV, the TLR9-MyD88-IRF7 pathway was necessary in CD11c(+) cells for the expression of proinflammatory cytokines and the recruitment of inflammatory monocytes (iMos) to the draining lymph node (dLN). In the dLN, the major producers of IFN-I were infected iMos, which used the DNA sensor-adaptor STING to activate IRF7 and nuclear factor κB (NF-κB) signaling to induce the expression of IFN-α and IFN-β, respectively. Thus, in vivo, two pathways of DNA pathogen sensing act sequentially in two distinct cell types to orchestrate resistance to a viral disease.
authors.affiliation: Immune Cell Development and Host Defense Program, The Research Institute at Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA.
authors.forename: Ren-Huan
authors.initials: RH
authors.lastname: Xu
authors.affiliation: Immune Cell Development and Host Defense Program, The Research Institute at Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA.
authors.forename: Eric B
authors.initials: EB
authors.lastname: Wong
authors.affiliation: Immune Cell Development and Host Defense Program, The Research Institute at Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Rubio
authors.affiliation: Immune Cell Development and Host Defense Program, The Research Institute at Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA.
authors.forename: Felicia
authors.initials: F
authors.lastname: Roscoe
authors.affiliation: Immune Cell Development and Host Defense Program, The Research Institute at Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA.
authors.forename: Xueying
authors.initials: X
authors.lastname: Ma
authors.affiliation: Immune Cell Development and Host Defense Program, The Research Institute at Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA.
authors.forename: Savita
authors.initials: S
authors.lastname: Nair
authors.affiliation: Immune Cell Development and Host Defense Program, The Research Institute at Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA.
authors.forename: Sanda
authors.initials: S
authors.lastname: Remakus
authors.affiliation: Institute of Molecular Cancer Research, University Zurich, 8057 Zurich, Switzerland.
authors.forename: Reto
authors.initials: R
authors.lastname: Schwendener
authors.affiliation: Department of Laboratory Medicine, Yale University, New Haven, CT 06520, USA.
authors.forename: Shinu
authors.initials: S
authors.lastname: John
authors.affiliation: Department of Immunology, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15261, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Shlomchik
authors.affiliation: Immune Cell Development and Host Defense Program, The Research Institute at Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA. Electronic address: luis.sigal@jefferson.edu.
authors.forename: Luis J
authors.initials: LJ
authors.lastname: Sigal
mesh_terms: D000818:Animals; D004266:DNA Virus Infections / Q000276:immunology; D004481:Ectromelia virus; D004482:Ectromelia, Infectious / Q000276:immunology; D005434:Flow Cytometry; D050839:Interferon Regulatory Factor-7 / Q000276:immunology; D007370:Interferon Type I / Q000096:biosynthesis / Q000276:immunology*; D008198:Lymph Nodes / Q000276:immunology; D008565:Membrane Proteins / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009000:Monocytes / Q000276:immunology*; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D051217:Toll-Like Receptor 9 / Q000276:immunology; D000099197:STING Protein
chemical_list: D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I; D008565:Membrane Proteins; D053594:Myeloid Differentiation Factor 88; D051217:Toll-Like Receptor 9; C494235:Irf7 protein, mouse; C507780:Myd88 protein, mouse; C530855:Sting1 protein, mouse; D000099197:STING Protein; C495370:Tlr9 protein, mouse