IRF1 Maintains Optimal Constitutive Expression of Antiviral Genes and Regulates the Early Antiviral Response

Panda, Debasis; Gjinaj, Erisa; Bachu, Mahesh; Squire, Erica; Novatt, Hilary; Ozato, Keiko; Rabin, Ronald L.

doi:10.3389/fimmu.2019.01019

IRF1 Maintains Optimal Constitutive Expression of Antiviral Genes and Regulates the Early Antiviral Response

Journal Article · Wed May 15 00:00:00 EDT 2019 · Frontiers in Immunology

DOI:https://doi.org/10.3389/fimmu.2019.01019· OSTI ID:1628046

Panda, Debasis ^[1]; Gjinaj, Erisa ^[2]; Bachu, Mahesh ^[3]; Squire, Erica ^[2]; Novatt, Hilary ^[2]; Ozato, Keiko ^[3]; Rabin, Ronald L. ^[2]

U.S. Food and Drug Administration (FDA), Silver Spring, MD (United States). Center for Biologics Evaluation and Research; DOE/OSTI
U.S. Food and Drug Administration (FDA), Silver Spring, MD (United States). Center for Biologics Evaluation and Research
Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD (United States)

Viral defense at mucosal sites depends on interferons (IFN) and IFN stimulated genes (ISGs), either of which may be constitutively expressed to maintain an “antiviral state” (AVS). However, the mechanisms that govern the AVS are poorly defined. Using a BEAS-2B respiratory epithelial cell line deficient in IRF1, we demonstrate higher susceptibility to infection with vesicular stomatitis virus (VSV) and influenza virus. IRF1-mediated restriction of VSV is IFN-independent, as blockade of types I and III IFNs and JAK-STAT signaling before infection did not affect VSV infection of either parent or IRF1 KO cells. Transcriptome analysis revealed that IRF1 regulates constitutive expression of ~300 genes, including antiviral ISGs: OAS2, BST2, and RNASEL and knockdown of any of these IRF1-dependent genes increased VSV infection. Additionally, IRF1 enhances rapid expression of IFNβ and IFNλ after stimulation with poly I:C and also regulates ISG expression. Mechanistically, IRF1 enhances recruitment of BRD4 to promotor-enhancer regions of ISGs for rapid expression and maintains levels of histone H3K4me1 for optimal constitutive expression. Finally, IRF1 also regulates constitutive expression of TLR2 and TLR3 and promotes signaling through these pattern recognition receptors (PRR). These data reveal multiple roles for IRF1 toward effective anti-viral responses by maintaining IFN-independent constitutive expression of anti-viral ISGs and supporting early IFN-dependent responses to PRR stimulation.

View Accepted Manuscript (DOE)

Research Organization:: Oak Ridge Institute for Science and Education (ORISE), Oak Ridge, TN (United States)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: SC0014664

OSTI ID:: 1628046

Journal Information:: Frontiers in Immunology, Journal Name: Frontiers in Immunology Vol. 10; ISSN 1664-3224

Publisher:: Frontiers Research FoundationCopyright Statement

Country of Publication:: United States

Language:: English

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epigenetic regulation
interferon independent
transcription factor

IRF1 Maintains Optimal Constitutive Expression of Antiviral Genes and Regulates the Early Antiviral Response

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