{"doi":"10.17615/hcy0-mn09","title":"IRF-3, IRF-5, and IRF-7 Coordinately Regulate the Type I IFN Response in Myeloid Dendritic Cells Downstream of MAVS Signaling","abstract":"Although the transcription factors IRF-3 and IRF-7 are considered master regulators of type I interferon (IFN) induction and IFN stimulated gene (ISG) expression, Irf3-/-×Irf7-/- double knockout (DKO) myeloid dendritic cells (mDC) produce relatively normal levels of IFN-β after viral infection. We generated Irf3-/-×Irf5-/-×Irf7-/- triple knockout (TKO) mice to test whether IRF-5 was the source of the residual induction of IFN-β and ISGs in mDCs. In pathogenesis studies with two unrelated positive-sense RNA viruses (West Nile virus (WNV) and murine norovirus), TKO mice succumbed at rates greater than DKO mice and equal to or approaching those of mice lacking the type I IFN receptor (Ifnar-/-). In ex vivo studies, after WNV infection or exposure to Toll-like receptor agonists, TKO mDCs failed to produce IFN-β or express ISGs. In contrast, this response was sustained in TKO macrophages following WNV infection. To define IRF-regulated gene signatures, we performed microarray analysis on WNV-infected mDC from wild type (WT), DKO, TKO, or Ifnar-/- mice, as well as from mice lacking the RIG-I like receptor adaptor protein MAVS. Whereas the gene induction pattern in DKO mDC was similar to WT cells, remarkably, almost no ISG induction was detected in TKO or Mavs-/- mDC. The relative equivalence of TKO and Mavs-/- responses suggested that MAVS dominantly regulates ISG induction in mDC. Moreover, we showed that MAVS-dependent induction of ISGs can occur through an IRF-5-dependent yet IRF-3 and IRF-7-independent pathway. Our results establish IRF-3, -5, and -7 as the key transcription factors responsible for mediating the type I IFN and ISG response in mDC during WNV infection and suggest a novel signaling link between MAVS and IRF-5.","journal":"UNC Libraries","year":2021,"id":230344,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9548,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":835563,"name":"S.C. Vick","orcid":null,"position":1,"is_corresponding":false},{"id":836747,"name":"M.M. Brassil","orcid":null,"position":2,"is_corresponding":false},{"id":836748,"name":"A.V. Moses","orcid":null,"position":3,"is_corresponding":false},{"id":836749,"name":"L. Clepper","orcid":null,"position":4,"is_corresponding":false},{"id":801371,"name":"M.S. Suthar","orcid":null,"position":5,"is_corresponding":false},{"id":836750,"name":"H.W. Virgin","orcid":null,"position":6,"is_corresponding":false},{"id":836751,"name":"A. Lancaster","orcid":null,"position":7,"is_corresponding":false},{"id":836752,"name":"K. Früh","orcid":null,"position":8,"is_corresponding":false},{"id":836753,"name":"L. Thackray","orcid":null,"position":9,"is_corresponding":false},{"id":836754,"name":"J. Nikolich-Zugich","orcid":null,"position":10,"is_corresponding":false},{"id":836755,"name":"C. Wilkins","orcid":null,"position":11,"is_corresponding":false},{"id":836756,"name":"A. Huang","orcid":null,"position":12,"is_corresponding":false},{"id":591480,"name":"H.M. Lazear","orcid":null,"position":13,"is_corresponding":false},{"id":590836,"name":"M.S. Diamond","orcid":null,"position":14,"is_corresponding":false},{"id":836746,"name":"M. Gale","orcid":null,"position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-18T23:55:05.844766Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}