title: Role of interferon regulatory factor 3 in type I interferon responses in rotavirus-infected dendritic cells and fibroblasts.
abstract: The main pathway for the induction of type I interferons (IFN) by viruses is through the recognition of viral RNA by cytosolic receptors and the subsequent activation of interferon regulatory factor 3 (IRF-3), which drives IFN-alpha/beta transcription. In addition to their role in inducing an antiviral state, type I IFN also play a role in modulating adaptive immune responses, in part via their effects on dendritic cells (DCs). Many viruses have evolved mechanisms to interfere with type I IFN induction, and one recently reported strategy for achieving this is by targeting IRF-3 for degradation, as shown for rotavirus nonstructural protein 1 (NSP1). It was therefore of interest to investigate whether rotavirus-exposed DCs would produce type I IFN and/or mature in response to the virus. Our results demonstrate that IRF-3 was rapidly degraded in rotavirus-infected mouse embryonic fibroblasts (MEFs) and type I IFN was not detected in these cultures. In contrast, rotavirus induced type I IFN production in myeloid DCs (mDCs), resulting in their activation. Type I IFN induction in response to rotavirus was reduced in mDCs from IRF-3(-/-) mice, indicating that IRF-3 was important for mediating the response. Exposure of mDCs to UV-treated rotavirus induced significantly higher type I IFN levels, suggesting that rotavirus-encoded functions also antagonized the response in DCs. However, in contrast to MEFs, this action was not sufficient to completely abrogate type I IFN induction, consistent with a role for DCs as sentinels for virus infection.
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Box 280, S-171 77 Stockholm, Sweden.
authors.forename: Iyadh
authors.initials: I
authors.lastname: Douagi
authors.forename: Gerald M
authors.initials: GM
authors.lastname: McInerney
authors.forename: Asa S
authors.initials: AS
authors.lastname: Hidmark
authors.forename: Vassoula
authors.initials: V
authors.lastname: Miriallis
authors.forename: Kari
authors.initials: K
authors.lastname: Johansen
authors.forename: Lennart
authors.initials: L
authors.lastname: Svensson
authors.forename: Gunilla B
authors.initials: GB
authors.lastname: Karlsson Hedestam
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003198:Computer Simulation; D003713:Dendritic Cells / Q000276:immunology* / Q000821:virology; D005347:Fibroblasts / Q000276:immunology* / Q000821:virology; D019085:Fluorescent Antibody Technique, Direct; D050838:Interferon Regulatory Factor-3 / Q000502:physiology*; D007370:Interferon Type I / Q000276:immunology*; D007739:L Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D012400:Rotavirus Infections / Q000276:immunology* / Q000378:metabolism
chemical_list: D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I