title: The IFN-independent response to virus particle entry provides a first line of antiviral defense that is independent of TLRs and retinoic acid-inducible gene I.
abstract: The innate immune system responds to pathogen infection by eliciting a nonspecific immune response following the recognition of various pathogen-associated molecular patterns. TLRs and the RNA helicases retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 recognize foreign nucleic acid within endosomal and cytoplasmic compartments, respectively, initiating a signaling cascade that involves the induction of type I IFN through the transcription factors IFN regulatory factor (IRF) 3 and NF-kappaB. However, a recent paradigm has emerged in which bacterial DNA and double-stranded B-form DNA trigger type I IFN production through an uncharacterized TLR- and RIG-I-independent pathway. We have previously described a response in primary fibroblasts wherein the entry of diverse RNA- and DNA-enveloped virus particles is sufficient to induce a subset of IFN-stimulated genes and a complete antiviral response in an IRF3-dependent, IFN-independent manner. In this study, we show that the innate immune response to virus particle entry is independent of both TLR and RIG-I pathways, confirming the existence of novel innate immune mechanisms that result in the activation of IRF3. Furthermore, we propose a model of innate antiviral immunity in which exposure to increasing numbers of virus particles elevates the complexity of the cellular response from an intracellular, IFN-independent response to one involving secretion of cytokines and activation of infiltrating immune cells.
authors.affiliation: Department of Pathology and Molecular Medicine, Center for Gene Therapeutics, McMaster University, 1200 Main Street West, Hamilton, Ontario, Canada.
authors.forename: Patrick
authors.initials: P
authors.lastname: Paladino
authors.forename: Derek T
authors.initials: DT
authors.lastname: Cummings
authors.forename: Ryan S
authors.initials: RS
authors.lastname: Noyce
authors.forename: Karen L
authors.initials: KL
authors.lastname: Mossman
mesh_terms: D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000276:immunology*; D004847:Epithelial Cells / Q000276:immunology / Q000382:microbiology; D005347:Fibroblasts / Q000276:immunology / Q000382:microbiology; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D006801:Humans; D007113:Immunity, Innate; D050838:Interferon Regulatory Factor-3 / Q000276:immunology*; D007372:Interferons; D018448:Models, Immunological; D016328:NF-kappa B; D011971:Receptors, Immunologic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051193:Toll-Like Receptors / Q000235:genetics / Q000276:immunology*; D014771:Virion / Q000276:immunology*
chemical_list: D050838:Interferon Regulatory Factor-3; D016328:NF-kappa B; D011971:Receptors, Immunologic; D051193:Toll-Like Receptors; D007372:Interferons; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases