HCV infection of adult hepatocytes results in temporally structured transcriptional responses which partially overlap with the IRF1 regulon
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE132548 | GEO | 2020/07/02
REPOSITORIES: GEO
Similar Datasets
Project description:HCV infection of adult hepatocytes results in temporally structured transcriptional responses which partially overlap with the IRF1 regulon
| PRJNA548340 | ENA
Project description:Transcriptional profiling provides global snapshots of virus-mediated cellular reprogramming, which can simultaneously encompass pro- and antiviral components. To determine early transcriptional signatures associated with HCV infection of authentic target cells, we performed ex vivo infections of adult primary human hepatocytes (PHHs) from seven donors. Coordinated sampling identified minimal gene dysregulation at six hours post infection (hpi) in PHHs. In contrast, at 72 hpi, massive increases in the breadth and magnitude of HCV-induced gene dysregulation were apparent, affecting gene classes associated with diverse biological processes. Comparison with HCV-induced transcriptional dysregulation in Huh-7.5 cells identified limited overlap between the two systems. Of note, in PHHs, HCV infection initiated broad upregulation of canonical interferon (IFN)-mediated defense programs, limiting viral RNA replication and abrogating virion release. In addition, we confirm that constitutive expression of IRF1 in PHHs maintains a steady-state antiviral program in the absence of infection which can further reduce HCV RNA replication. We also detected infection-induced signatures of translational shutoff in PHHs - downregulation of ~90 genes encoding components of the EIF2 translation initiation complex and ribosomal subunits. As HCV polyprotein translation occurs independently of the EIF2 complex, this process is pro-viral: only translation initiation of host transcripts is arrested. The combination of antiviral intrinsic and inducible immunity, balanced against pro-viral programs, including translational arrest, maintains HCV replication at a low-level in PHHs. This may ultimately keep HCV under the radar of extra-hepatocyte immune surveillance while initial infection is established, promoting tolerance, preventing clearance and facilitating progression to chronicity.
2021-03-02 | GSE166428 | GEO
Project description:Inborn errors of human IFN-γ immunity underlie mycobacterial diseases, whereas inborn errors of IFN-a/b immunity underlie viral diseases. Both types of IFNs induce the transcription factor IRF1. We describe two unrelated children with inherited complete IRF1 deficiency and early-onset, multiple, life-threatening diseases caused by weakly virulent mycobacteria. These children have no history of severe viral disease, despite exposure to many viruses, including SARS-CoV-2, which is life-threatening in individuals with impaired IFN-a/b immunity. The IRF1-dependent cellular responses to IFN-γ are, both quantitatively and qualitatively, much greater than those to IFN-a/b in vitro. Monocyte- and iPSC-derived macrophages from the two patients show no upregulation of at least 20% of the target genes normally induced by IFN-γ. By contrast, cell-intrinsic IFN-a/b immunity to diverse viruses, including SARS-CoV-2, is intact. Human IRF1 is, thus, largely redundant for antiviral IFN-a/b immunity. By contrast, human IRF1 is essential for IFN-γ immunity to mycobacteria in myeloid cells.
2023-01-19 | PXD037759 | Pride
Project description:Inborn errors of human IFN-γ-dependent macrophagic immunity underlie mycobacterial diseases, whereas inborn errors of IFN-α/β-dependent intrinsic immunity underlie viral diseases. Both types of IFNs induce the transcription factor IRF1. We describe unrelated children with inherited complete IRF1 deficiency and early-onset, multiple, life-threatening diseases caused by weakly virulent mycobacteria and related intramacrophagic pathogens. These children have no history of severe viral disease, despite exposure to many viruses, including SARS-CoV-2, which is life-threatening in individuals with impaired IFN-α/β immunity. In leukocytes or fibroblasts stimulated in vitro, IRF1-dependent responses to IFN-γ are, both quantitatively and qualitatively, much stronger than those to IFN-α/β. Moreover, IRF1-deficient mononuclear phagocytes do not control mycobacteria and related pathogens normally when stimulated with IFN-γ. By contrast, IFN-α/β-dependent intrinsic immunity to nine viruses, including SARS-CoV-2, is almost normal in IRF1-deficient fibroblasts. Human IRF1 is essential for IFN-γ-dependent macrophagic immunity to mycobacteria, but largely redundant for IFN-α/β-dependent antiviral immunity.
2023-05-12 | GSE203220 | GEO
Project description:Inborn errors of human IFN-γ immunity underlie mycobacterial diseases, whereas inborn errors of IFN-/ immunity underlie viral diseases. Both types of IFNs induce the transcription factor IRF1. We describe two unrelated children with inherited complete IRF1 deficiency and early-onset, multiple, life-threatening diseases caused by weakly virulent mycobacteria. These children have no history of severe viral disease, despite exposure to many viruses, including SARS-CoV-2, which is life-threatening in individuals with impaired IFN-/ immunity. The IRF1-dependent cellular responses to IFN-γ are, both quantitatively and qualitatively, much greater than those to IFN-/ in vitro. Monocyte- and iPSC-derived macrophages from the two patients show no upregulation of at least 20% of the target genes normally induced by IFN-γ. By contrast, cell-intrinsic IFN-/ immunity to diverse viruses, including SARS-CoV-2, is intact. Human IRF1 is, thus, largely redundant for antiviral IFN-/ immunity. By contrast, human IRF1 is essential for IFN-γ immunity to mycobacteria in myeloid cells.
2023-01-12 | GSE218033 | GEO
Project description:Oncolytic viruses exploit common molecular changes in cancer cells, which are not present in normal cells, to target and kill cancer cells. Ras transformation and defects in type I interferon (IFN)-mediated antiviral responses are known to be the major mechanisms underlying viral oncolysis. Previously, we demonstrated that oncogenic RAS/Mitogen-activated protein kinase kinase (Ras/MEK) activation suppresses the transcription of many IFN-inducible genes in human cancer cells, suggesting that Ras transformation underlies type I IFN defects in cancer cells. Here, we investigated how Ras/MEK downregulates IFN-induced transcription. By conducting promoter deletion analysis of IFN-inducible genes, namely guanylate-binding protein 2 and IFN gamma inducible protein 47 (Ifi47), we identified the IFN regulatory factor 1 (IRF1) binding site as the promoter region responsible for the regulation of transcription by MEK. MEK inhibition promoted transcription of the IFN-inducible genes in wild type mouse embryonic fibroblasts (MEFs), but not in IRF1?/? MEFs, showing that IRF1 is involved in MEK-mediated downregulation of IFN-inducible genes. Furthermore, IRF1 protein expression was lower in RasV12 cells compared with vector control NIH3T3 cells, but was restored to equivalent levels by inhibition of MEK. Similarly, the restoration of IRF1 expression by MEK inhibition was observed in human cancer cells. IRF1 re-expression in human cancer cells caused cells to become resistant to infection by the oncolytic vesicular stomatitis virus strain. Together, this work demonstrates that Ras/MEK activation in cancer cells downregulates transcription of IFN-inducible genes by targeting IRF1 expression, resulting in increased susceptibility to viral oncolysis. RNA was isolated from RasV12 transformed NIH/3T3 cells (RasV12 cells) treated with 20?M U0126 or 500U/ml IFN-?, or left untreated, for 6 hours, triplicate biological samples (9 samples).
2014-11-13 | E-GEOD-49469 | biostudies-arrayexpress
Project description:Type I interferons (IFN-I) and IFN- foster antitumor immunity by facilitating T cell responses. Paradoxically, IFNs may promote T cell exhaustion by activating immune checkpoints. The downstream regulators of these responses are incompletely understood. Herein, we describe how Interferon Regulatory Factor 1 (IRF1) orchestrates these opposing effects of IFNs. IRF1 expression in tumors blocked Toll-like receptor and IFN-I-dependent host antitumor immunity by preventing IFN stimulated gene (ISG) programs and effector programs in dendritic cells and T cells. In contrast, expression of IRF1 in the host, but not IRF3 or IFN-, was also required for antitumor immunity to wildtype and Irf1-/- tumors. Mechanistically, tumor cell IRF1 regulated major histocompatibility class I expression and bound uniquely or together with STAT1 at many ISGs, contributing to expression of immunosuppressive but not immunostimulatory ISGs. Overexpression of PD-L1 in Irf1-/- tumors only partially restored tumor growth, suggesting that the negative effects of tumor IRF1 on antitumor immunity are multifactorial. Thus, we identify tumor cell IRF1 expression as a previously unrecognized selective inhibitor of host IFN-I dependent antitumor immunity, while host IRF1 and IFN-I are critical drivers of antitumor immune responses.
2024-05-01 | GSE246923 | GEO
Project description:IRF1, and interferon-induced transcription factor, was found to have antiviral activity against a range of viruses when overexpressed. To determine which genes are associated with expression of IRF1, gene expression analysis was carried out in two different cell line expressing IRF1. The results show that more than 100 genes, many of which overlap with type I interferon-stimulated genes, are induced more than 3-fold by IRF1. A majority of the genes were induced in both cell types, while some genes were highly induced in a cell type-specific manner. To investigate the impact of IRF1 overexpression on the transriptome of two target cell lines, cells were transduced with a lentiviral vector expressing IRF1 or Firefly luciferase (Fluc) as a control. Total mRNA was harvested 48 h post-transduction and processed for Illumina BeadArray analysis. Skin fibroblast cell line described in Dupuis, S. et al., Impaired response to interferon-alpha/beta and lethal viral disease in human STAT1 deficiency. Nat Genet 33 (3), 388 (2003)
2011-04-01 | E-GEOD-26817 | biostudies-arrayexpress
Project description:Although the core type I and type II IFN signaling pathways are distinct, their expression profiles show considerable overlap and are difficult to discern. Using a genome-wide RNAseq-ChIPseq integrative approach, our results identify a novel class of IFN-I and IFN-II responsive genes that use ISRE and GAS composite sites to recruit STAT1 and STAT2-containing ISGF3 and GAF-like complexes and IRF1 for optimal expression. Moreover, they support the existence of an analogous transcriptional regulatory mechanism of IFNα and IFNγ inducible genes, in which STAT1 and STAT2-containing ISGF3 and GAF-like complexes and IRF1 are recruited to individual or combined ISRE and GAS composite sites in an IFN- and time-dependent manner. In addition, we present proof for the involvement of an ISRE and GAS composite-dependent regulatory system in IFN-activated positive feedback regulation of the STAT1, STAT2, IRF9 and IRF1 genes and long-term response to IFNs, which depends on phosphorylation and expression of ISGF3, IRF1 and GAF-like components. These findings provide further insight in the existence of a novel intracellular amplifier circuit that offer an explanation for the existing molecular and functional overlap between IFN-I and IFN-II activated ISG expression.
2023-05-04 | GSE222667 | GEO
Project description:Although the core type I and type II IFN signaling pathways are distinct, their expression profiles show considerable overlap and are difficult to discern. Using a genome-wide RNAseq-ChIPseq integrative approach, our results identify a novel class of IFN-I and IFN-II responsive genes that use ISRE and GAS composite sites to recruit STAT1 and STAT2-containing ISGF3 and GAF-like complexes and IRF1 for optimal expression. Moreover, they support the existence of an analogous transcriptional regulatory mechanism of IFNα and IFNγ inducible genes, in which STAT1 and STAT2-containing ISGF3 and GAF-like complexes and IRF1 are recruited to individual or combined ISRE and GAS composite sites in an IFN- and time-dependent manner. In addition, we present proof for the involvement of an ISRE and GAS composite-dependent regulatory system in IFN-activated positive feedback regulation of the STAT1, STAT2, IRF9 and IRF1 genes and long-term response to IFNs, which depends on phosphorylation and expression of ISGF3, IRF1 and GAF-like components. These findings provide further insight in the existence of a novel intracellular amplifier circuit that offer an explanation for the existing molecular and functional overlap between IFN-I and IFN-II activated ISG expression.
2023-05-04 | GSE221804 | GEO