Human IFIT3 Protein Induces Interferon Signaling and Inhibits Adenovirus Immediate Early Gene Expression

Chikhalya, Aniska; Dittmann, Meike; Zheng, Yongchun; Sohn, Sook-Young; Rice, Charles M.; Hearing, Patrick

doi:10.1128/mbio.02829-21

Cited by 28 publications

(32 citation statements)

References 49 publications

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“…Elevated TLR3 expression indicates the recognition of the dsRNA mimetic by the cell, and the subsequent activation of TLR3 downstream signaling indicates that ALOS4 does not prevent the entry of the virus-like agent. At the same time, pretreatment with ALOS4 affects the expression of IFN-α and IFN-λ (Figure 1D; one-way ANOVA, followed by Tukey's means separation test for ALOS4 + Poly I:C vs. Poly I:C: IFN-α, p = 0.0058; IFN-λ, p = 0.0011) and stimulates a strong increase in interferon-induced protein with tetratricopeptide repeats 3 (IFIT3), known for its important role in antiviral signaling [33], possibly via IRF3 activation (Figure 1C). This hypothesis is supported by the previously described phenomenon that, independent of interferon, IRF3 induces the upregulation of interferon-stimulated genes in a human CMV model [34].…”

Section: Resultsmentioning

confidence: 99%

Targeted Modulation of Interferon Response-Related Genes with IFN-Alpha/Lambda Inhibition

Sur

Leonova

Levi

et al. 2022

IJMS

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Interferon (IFN) signaling resulting from external or internal inflammatory processes initiates the rapid release of cytokines and chemokines to target viral or bacterial invasion, as well as cancer and other diseases. Prolonged exposure to IFNs, or the overexpression of other cytokines, leads to immune exhaustion, enhancing inflammation and leading to the persistence of infection and promotion of disease. Hence, to control and stabilize an excessive immune response, approaches for the management of inflammation are required. The potential use of peptides as anti-inflammatory agents has been previously demonstrated. Our team discovered, and previously published, a 9-amino-acid cyclic peptide named ALOS4 which exhibits anti-cancer properties in vivo and in vitro. We suggested that the anti-cancer effect of ALOS4 arises from interaction with the immune system, possibly through the modulation of inflammatory processes. Here, we show that treatment with ALOS4 decreases basal cytokine levels in mice with chronic inflammation and prolongs the lifespan of mice with acute systemic inflammation induced by irradiation. We also show that pretreatment with ALOS4 reduces the expression of IFN alpha, IFN lambda, and selected interferon-response genes triggered by polyinosinic-polycytidylic acid (Poly I:C), a synthetic analog of viral double-stranded RNA, while upregulating the expression of other genes with antiviral activity. Hence, we conclude that ALOS4 does not prevent IFN signaling, but rather supports the antiviral response by upregulating the expression of interferon-response genes in an interferon-independent manner.

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Section: Resultsmentioning

confidence: 99%

Targeted Modulation of Interferon Response-Related Genes with IFN-Alpha/Lambda Inhibition

Sur

Leonova

Levi

et al. 2022

IJMS

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“…Earlier reports have reported these ISGs ( 30 , 34 ). IFIT1 and IFIT3 belong to the IFN-induced protein with the tetratricopeptide repeats (IFIT) family ( 35 ). IFIT3 expression in human diploid fibroblasts cells activates TBK1 and IRF3, causing the production of IFN-β, activation of STAT1, and induction of ISGs expression ( 35 ).…”

Section: Discussionmentioning

confidence: 99%

“…IFIT1 and IFIT3 belong to the IFN-induced protein with the tetratricopeptide repeats (IFIT) family ( 35 ). IFIT3 expression in human diploid fibroblasts cells activates TBK1 and IRF3, causing the production of IFN-β, activation of STAT1, and induction of ISGs expression ( 35 ). RSAD2, also known as Viperin, is a highly induced ISG and plays an intermediary role in inducing pDCs to generate IFN-I by mediating TLR7 and TLR9 ( 36 ).…”

Section: Discussionmentioning

confidence: 99%

Identification of key interferon-stimulated genes for indicating the condition of patients with systemic lupus erythematosus

et al. 2022

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Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with highly heterogeneous clinical symptoms and severity. There is complex pathogenesis of SLE, one of which is IFNs overproduction and downstream IFN-stimulated genes (ISGs) upregulation. Identifying the key ISGs differentially expressed in peripheral blood mononuclear cells (PBMCs) of patients with SLE and healthy people could help to further understand the role of the IFN pathway in SLE and discover potential diagnostic biomarkers.The differentially expressed ISGs (DEISG) in PBMCs of SLE patients and healthy persons were screened from two datasets of the Gene Expression Omnibus (GEO) database. A total of 67 DEISGs, including 6 long noncoding RNAs (lncRNAs) and 61 messenger RNAs (mRNAs) were identified by the “DESeq2” R package. According to Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, those DEISGs were mainly concentrated in the response to virus and immune system processes. Protein-protein interaction (PPI) network showed that most of these DEISGs could interact strongly with each other. Then, IFIT1, RSAD2, IFIT3, USP18, ISG15, OASL, MX1, OAS2, OAS3, and IFI44 were considered to be hub ISGs in SLE by “MCODE” and “Cytohubba” plugins of Cytoscape, Moreover, the results of expression correlation suggested that 3 lncRNAs (NRIR, FAM225A, and LY6E-DT) were closely related to the IFN pathway.The lncRNA NRIR and mRNAs (RSAD2, USP18, IFI44, and ISG15) were selected as candidate ISGs for verification. RT-qPCR results showed that PBMCs from SLE patients had substantially higher expression levels of 5 ISGs compared to healthy controls (HCs). Additionally, statistical analyses revealed that the expression levels of these ISGs were strongly associated to various clinical symptoms, including thrombocytopenia and facial erythema, as well as laboratory indications, including the white blood cell (WBC) count and levels of autoantibodies. The Receiver Operating Characteristic (ROC) curve demonstrated that the IFI44, USP18, RSAD2, and IFN score had good diagnostic capabilities of SLE.According to our study, SLE was associated with ISGs including NRIR, RSAD2, USP18, IFI44, and ISG15, which may contribute to the future diagnosis and new personalized targeted therapies.

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“…IFIT3 is an interferon-inducible protein with a tetrapeptide repeat sequence. Various pathogens, especially DNA and RNA viruses, can induce IFIT3 expression, and IFIT3 performs antiviral defense ( 34 , 35 ). However, the mechanism of its interaction with viral hepatitis-associated liver fibrosis needs to be further investigated.…”

Section: Discussionmentioning

confidence: 99%

Exploration of immune infiltration and feature genes in viral hepatitis-associated liver fibrosis using transcriptome data

Pan¹,

Tian²,

Hu³

et al. 2022

Ann Transl Med

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Background: Immune cells play an essential role in virus-induced liver fibrosis. However, the underlying mechanisms remain unclear. In this study, we systematically explored immune cell infiltration and feature genes to provide new insights into viral hepatitis-associated liver fibrosis. Methods:The expression datasets GSE14323, GSE33650, GSE6764 (for testing), and GSE84044 (for validation) were downloaded from the Gene Expression Omnibus (GEO) database. Immune cell infiltration was assessed using the CIBERSORT algorithm, and characteristic subgroups were obtained using least absolute shrinkage and selection operator (LASSO) regression and Wilcox Text. The association between feature genes and immune-infiltrating cells was explored using Spearman's correlation analysis. R software and IBM SPSS Statistics were utilized for data analysis and visualization.Results: We identified 10 differential immune cells between viral hepatitis-associated liver fibrosis and non-fibrosis, including naive B cells, plasma cells, resting CD4+ memory T cells, T follicular helper (Tfh) cells, regulatory T (Treg) cells, M0-M2 macrophages, and resting and activated mast cells. Six feature genes were identified: STAT1, CXCL10, PTPRC, IFIT3, OAS2, and MX1. They also differed significantly in the subgroups of non-fibrosis, mild to moderate fibrosis and severe fibrosis. Both the feature genes and immune cells were verified in the validation group. All the genes were positively associated with macrophages M1 and negatively associated with macrophages M2. Conclusions:The six feature genes may be involved in viral hepatitis-associated liver fibrosis by promoting the polarization of macrophages from M0 to M1 and inhibiting their conversion to M2. Thus, these genes may serve as potential therapeutic targets.

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Human IFIT3 Protein Induces Interferon Signaling and Inhibits Adenovirus Immediate Early Gene Expression

Cited by 28 publications

References 49 publications

Targeted Modulation of Interferon Response-Related Genes with IFN-Alpha/Lambda Inhibition

Targeted Modulation of Interferon Response-Related Genes with IFN-Alpha/Lambda Inhibition

Identification of key interferon-stimulated genes for indicating the condition of patients with systemic lupus erythematosus

Exploration of immune infiltration and feature genes in viral hepatitis-associated liver fibrosis using transcriptome data

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