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

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.

Global Spread of SARS-CoV-2 Subtype with Spike Protein Mutation D614G is Shaped by Human Genomic Variations that Regulate Expression ofTMPRSS2andMX1Genes

“…IRF1 and IRF2 are antagonistic to each other (55,56,58), but help maintain a fine balance in expression of both MX1 and TMPRSS2. Loss of IRF2 recognition site, due to rs35074065-delC variant, leads to increased IRF1 mediated expression of MX1 (53). Recent analysis by Human Lung Cell Atlas group identified that ACE2 and TMPRSS2 are interferon regulated and ACE2+ TMPRSS2+ Single cells that express both ACE2 and TMPRSS2, also express innate immunity associated genes like MX1, IDO1, etc.…”

“…We bioinformatically identified transcription factor binding sites around the rs35074065 locus. A recognition site for transcription factor IRF1 (Interferon Regulatory Factor 1), which is known to activate MX1 (53), was present in the sequences -containing the reference (C) and the variant (delC) alleles -around the rs35074065 eQTL. IRF1 is known to activate genes in response to viruses (54).…”

Integrative Network Analysis of Predicted miRNA-Targets Regulating Expression of Immune Response Genes in Bovine Coronavirus Infection

“…Increased expression of CEBPD also elevates the expression of IL-6 (Hungness et al, 2002). IRF1 mediates both innate and adaptive responses to viral infection such as inducing apoptosis and restricting viral replication (Kanazawa et al, 2004;Kung et al, 2014;Nair et al, 2017;Panda et al, 2019). Both target genes are highly indicated in the immune related pathways found FIGURE 8 | Bar chart representing the number of genes indicated in each of the significant and specific immune-related pathways found using GO and GeneAnalytics.…”

“…They are responsible for the ongoing COVID-19 pandemic and the attendant significant morbidity and mortality (Gussow et al, 2020;Lucas et al, 2020). Bovine coronavirus (BCoV) is endemic worldwide and affects both wild and domesticated cattle (Saif, 2010), causing disease affecting the respiratory system and gastrointestinal tract, with pathogenesis ranging from mild to fatal (Underwood et al, 2015;Oma et al, 2016). BCoV has high mortality rates in calves, inducing wasting and flattening of the villi in the GI and a substantial cause of calf diarrhea.…”

“…Bovine coronavirus is transmitted via the respiratory or oralfecal route, and it has been documented that recurrent nasal shedding occurs in infected cattle. Infection is detected using fecal or nasal swabs analyzed via real-time reverse transcriptasepolymerase chain reactions (RT-PCR) that detect nucleocapsid (N) or transmembrane (M) protein-coding genes of the virus (Takiuchi et al, 2006;Decaro et al, 2008;Oma et al, 2016). BCoV has a highly glycosylated spike (S) protein as well as a hemagglutinin esterase (HE), both major participants in the attachment of the virus to the host cell (Saif and Jung, 2020).…”