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

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

doi:10.3389/fimmu.2019.01019

Abstract

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.

Highlights

Airway epithelial cells are targets for viral replication and provide the first line of defense against virus entry and infection
Since IRF7 is not constitutively expressed by respiratory epithelial cells, their antiviral defenses may lag behind expression of viral encoded antagonists of antiviral IFN stimulated genes (ISGs)
Respiratory epithelial cells must rely on alternative mechanisms, such as enhanced basal expression of ISGs, to block viral replication

Summary

Introduction

Airway epithelial cells are targets for viral replication and provide the first line of defense against virus entry and infection. The interaction between viral pathogens and epithelial cells often determines the outcome of viral infection, either directly or by modulating the subsequent adaptive immune response. Since viral pathogens express proteins to block IFN and ISG functions, innate antiviral immunity is IRF1 Regulates IFN-Independent Antiviral Response only effective when rapidly implemented. To give the host a head-start, cells acquire an “antiviral state” by expressing ISGs constitutively (i.e., independent of IFNs) or in response to constitutive expression of IFNβ [3,4,5]. IFN-independent constitutive expression of ISGs is appealing because the AVS is acquired without the detrimental bystander effects associated with aberrant IFN expression [6]. While the benefits of an IFN-independent AVS are known, molecular mechanisms that regulate it remain undefined

Methods

Results

Conclusion