title: Salmonella Typhimurium Co-Opts the Host Type I IFN System To Restrict Macrophage Innate Immune Transcriptional Responses Selectively.
abstract: Innate immune inflammatory responses are subject to complex layers of negative regulation at intestinal mucosal surfaces. Although the type I IFN system is critical for amplifying antiviral immunity, it has been shown to play a homeostatic role in some models of autoimmune inflammation. Type I IFN is triggered in the gut by select bacterial pathogens, but whether and how the type I IFN might regulate innate immunity in the intestinal environment have not been investigated in the context of Salmonella enterica serovar Typhimurium (ST). ST infection of human or murine macrophages reveals that IFN-β selectively restricts the transcriptional responses mediated by both the TLRs and the NOD-like receptors. Specifically, IFN-β potently represses ST-dependent innate induction of IL-1 family cytokines and neutrophil chemokines. This IFN-β-mediated transcriptional repression was independent of the effects of IFN-β on ST-induced macrophage cell death, but significantly dependent on IL-10 regulation. We further evaluated ST pathogenesis in vivo following oral inoculation of mice lacking IFN-β. We show that IFN-β(-/-) mice exhibit greater resistance to oral ST infection and a slower spread of ST to distal sterile sites. This work provides mechanistic insight into the relationship between ST and type I IFN, and demonstrates an additional mechanism by which IFN-β may promote spread of enteric pathogens.
authors.affiliation: Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201; and dperkins@som.umaryland.edu.
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Perkins
authors.affiliation: Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201; and.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Rajaiah
authors.affiliation: Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD 21201.
authors.forename: Sharon M
authors.initials: SM
authors.lastname: Tennant
authors.affiliation: Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD 21201.
authors.forename: Girish
authors.initials: G
authors.lastname: Ramachandran
authors.affiliation: Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD 21201.
authors.forename: Ellen E
authors.initials: EE
authors.lastname: Higginson
authors.affiliation: Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201; and.
authors.forename: Tristan N
authors.initials: TN
authors.lastname: Dyson
authors.affiliation: Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201; and.
authors.forename: Stefanie N
authors.initials: SN
authors.lastname: Vogel
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D018925:Chemokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology*; D054884:Host-Pathogen Interactions / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007082:Ileum / Q000166:cytology; D007113:Immunity, Innate / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D016899:Interferon-beta / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012481:Salmonella Infections, Animal / Q000235:genetics / Q000276:immunology / Q000382:microbiology; D012486:Salmonella typhimurium / Q000276:immunology* / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D018925:Chemokines; D016207:Cytokines; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D016899:Interferon-beta