IRF-3, IRF-5, and IRF-7 Coordinately Regulate the Type I IFN Response in Myeloid Dendritic Cells Downstream of MAVS Signaling

Helen M. Lazear, Alissa Lancaster, Courtney Wilkins, Mehul S. Suthar, Albert Huang, Sarah C. Vick, Lisa Clepper, Larissa Thackray, Margaret M. Brassil, Herbert W. Virgin, Janko Nikolich-Zugich, Ashlee V. Moses, Michael Gale, Klaus Früh, Michael S. Diamond

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170 Scopus citations

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.

Original languageEnglish (US)
Article numbere1003118
JournalPLoS pathogens
Volume9
Issue number1
DOIs
StatePublished - Jan 1 2013

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ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

Cite this

Lazear, H. M., Lancaster, A., Wilkins, C., Suthar, M. S., Huang, A., Vick, S. C., Clepper, L., Thackray, L., Brassil, M. M., Virgin, H. W., Nikolich-Zugich, J., Moses, A. V., Gale, M., Früh, K., & Diamond, M. S. (2013). IRF-3, IRF-5, and IRF-7 Coordinately Regulate the Type I IFN Response in Myeloid Dendritic Cells Downstream of MAVS Signaling. PLoS pathogens, 9(1), [e1003118]. https://doi.org/10.1371/journal.ppat.1003118