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IRF-3, IRF-5, and IRF-7 coordinately regulate the type I IFN response in myeloid dendritic cells downstream of MAVS signaling.
Title | IRF-3, IRF-5, and IRF-7 coordinately regulate the type I IFN response in myeloid dendritic cells downstream of MAVS signaling. |
Publication Type | Journal Article |
Year of Publication | 2013 |
Authors | Lazear, HM, Lancaster, A, Wilkins, C, Suthar, MS, Huang, A, Vick, SC, Clepper, L, Thackray, L, Brassil, MM, Virgin, HW, Nikolich-Zugich, J, Moses, AV, Gale, M, Früh, K, Diamond, MS |
Journal | PLoS Pathog |
Volume | 9 |
Issue | 1 |
Pagination | e1003118 |
Date Published | 2013 Jan |
ISSN | 1553-7374 |
Keywords | Adaptor Proteins, Signal Transducing, Animals, Dendritic Cells, Interferon Regulatory Factor-3, Interferon Regulatory Factor-7, Interferon Regulatory Factors, Interferon-beta, Macrophages, Mice, Mice, Inbred C57BL, Mice, Knockout, Myeloid Cells, Receptor, Interferon alpha-beta, Signal Transduction, Toll-Like Receptors, Viral Load, West Nile Fever, West Nile virus |
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. |
DOI | 10.1371/journal.ppat.1003118 |
Alternate Journal | PLoS Pathog. |
PubMed ID | 23300459 |