Transcriptional Responses of Human Intestinal Organoids to Interferon Types I, II, and III
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE190899 | GEO | 2021/12/21
REPOSITORIES: GEO
Similar Datasets
Project description:RNAseq of intestinal epithelial cell (IEC) organoids and treated with PBS, interferon beta (IFNB), or interferon lambda (IFNL). RNAseq of IECs sorted from neonatal mouse intestines following treatment with PBS, IFNB, or IFNL.
2019-12-18 | GSE142166 | GEO
Project description:Treating inflammatory diseases with Janus kinase 1/2 (JAK1/2) inhibitors bears the risk that patients acquire viral infections due to unwanted immune suppression. Tyrosine kinase 2 (TYK2), a JAK family member, is required for type I interferon (IFN-α/β) signaling, but its role in type III IFN (IFN-λ) signaling is still under debate. We found that the selective TYK2 inhibitor BMS-986165 blocked potentially noxious type I IFN signaling without altering IFN-λ-mediated gene expression. We show that epithelial cells do not require TYK2 for IFN-λ-mediated signaling or antiviral protection. Lack of TYK2 diminished IFN-α-induced protection against lethal influenza virus infection of mice, but did not impair IFN-λ-mediated antiviral protection. Our findings suggest that selective TYK2 inhibitors likely represent a superior treatment option for type I interferonopathies than broadly acting JAK1/2 inhibitors, as selective TYK2 inhibitors may counteract inflammatory responses without abolishing the beneficial antiviral effects of IFN-λ.
2021-04-09 | GSE146103 | GEO
Project description:Treating inflammatory diseases with Janus kinase 1/2 (JAK1/2) inhibitors bears the risk that patients acquire viral infections due to unwanted immune suppression. Tyrosine kinase 2 (TYK2), a JAK family member, is required for type I interferon (IFN-α/β) signaling, but its role in type III IFN (IFN-λ) signaling is still under debate. We found that the selective TYK2 inhibitor BMS-986165 blocked potentially noxious type I IFN signaling without altering IFN-λ-mediated gene expression. We show that epithelial cells do not require TYK2 for IFN-λ-mediated signaling or antiviral protection. Lack of TYK2 diminished IFN-α-induced protection against lethal influenza virus infection of mice, but did not impair IFN-λ-mediated antiviral protection. Our findings suggest that selective TYK2 inhibitors likely represent a superior treatment option for type I interferonopathies than broadly acting JAK1/2 inhibitors, as selective TYK2 inhibitors may counteract inflammatory responses without abolishing the beneficial antiviral effects of IFN-λ.
2021-04-09 | GSE146102 | GEO
Project description:Although type III interferons (IFN), also known as IFN-λ or IL28/IL-29, restrict infection by several viruses, their mechanism of inhibitory action has remained uncertain. We used recombinant IFN-λ and mice lacking the IFN-λ receptor (IFNLR1) to evaluate the effect of IFN-λ on infection with West Nile virus (WNV), an encephalitic flavivirus. Cell culture studies in keratinocytes and dendritic cells showed no direct antiviral effect of exogenous IFN-λ even though ISGs were induced. Correspondingly, we observed no differences in WNV burden between wild-type and Ifnlr1-/- mice in the draining lymph node, spleen, and blood. However, we detected earlier dissemination and increased WNV infection in the brain and spinal cord of Ifnlr1-/- mice, yet this was not associated with a direct antiviral effect on infection of neurons. Instead, an increase in blood-brain barrier (BBB) permeability was observed in Ifnlr1-/- mice. Accordingly, treatment of mice with pegylated IFN-λ2 resulted in decreased BBB permeability, reduced WNV infection in the brain without impacting viremia, and improved survival against lethal virus challenge. An in vitro model of the BBB showed that IFN-λ signaling in brain microvascular endothelial cells increased transendothelial electrical resistance, decreased virus movement across the barrier, and modulated tight junction protein localization in a protein synthesis- and STAT1-independent manner. Our data establish a novel indirect antiviral function of IFN-λ in which non-canonical signaling through IFNLR1 tightens the BBB and restricts viral neuroinvasion and pathogenesis. This finding suggests new clinical applications for IFN-λ in treating viral or autoimmune diseases. Transcriptome profiling of bone-marrow derived Dendritic cells(BMDCs), treated with either Serum Free Media(Mock), interferon beta(IFNb), or interferon lambda(IFNL) for 6 hours.
2015-01-08 | E-GEOD-64735 | biostudies-arrayexpress
Project description:Type III interferon (IFN-λ) is known to be a potential immune modulator, but the mechanisms behind its immune-modulatory functions and its impact on plasmablast differentiation in humans, remain unknown. Human B-cells and their subtypes directly respond to IFN-λ. We performed B-cell transcriptome profiling to investigate the immune-modulatory role of IFN-λ in B-cells. We found that IFN-λ induced gene expression in B cells is steady, prolonged and importantly cell type-specific. Further, IFN-λ enhances the mTORC1 (mammalian/mechanistic target 34 of rapamycin complex 1) pathway in the B-cell receptor-activated B-cells (BCR/anti-IgM). The engagement of mTORC1 by BCR and IFN-lambda induces the cell cycle progress in B-cells. Subsequently, IFN-λ boosts the differentiation of naïve B-cells into plasmablast upon activation and the cells gain effector functions such as cytokine release (IL-6, IL-10) and antibody production. Our study shows how IFN-λ systematically boosts the differentiation of naïve B-cells into plasmablasts by enhancing the mTORC1 pathway and cell cycle progression in activated B-cells, which is a previously unknown immune modulatory role of IFN-λ.
2020-08-14 | GSE156195 | GEO
Project description:<p>The precise mechanism by which butyrate-producing bacteria in the gut contribute to resistance to respiratory viral infections remains to be elucidated. Here, we describe a gut-lung axis mechanism and report that orally administered Clostridium butyricum (CB) enhances influenza virus infection resistance through upregulation of interferon (IFN)-λ in lung epithelial cells. Gut microbiome-induced ω-3 fatty acid 18-hydroxy eicosapentaenoic acid (18-HEPE) promotes IFN-λ production through the G protein-coupled receptor (GPR)120 and IFN regulatory factor (IRF)-1/-7 activations. CB promotes 18-HEPE production in the gut and enhances ω-3 fatty acid sensitivity in the lungs by promoting GPR120 expression. This study finds a gut-lung axis mechanism and provides insights into the treatments and prophylaxis for viral respiratory infections.</p>
2023-05-30 | MTBLS4590 | MetaboLights
Project description:To expand knowledge of the effects of interferon at the proteomic level, we treated HepG2 cells with IFN-alpha and IFN-lambda for 24 hours. HepG2.2.15 cells, a model for HBV infection, were also examined versus controls. MTT assays showed that optimized IFN levels (100 ng/ml) did not induce apoptosis relative to untreated controls. Including controls, more than 6,000 proteins were identified. Five replicates each of IFN-alpha treatment, IFN-lambda treatment, and control were performed, allowing confident identification of differentially expressed proteins. While a number of publications suggest that no interferon effect is evident upon HBV infection, our own results strongly suggest otherwise. Differential alterations of the proteasome were noted when comparing HBV infection against IFN-treatment. We also note that differential effects upon IFN treatment significantly overlapped with transcriptomic datasets when upregulation was examined. However, proteins downregulated upon IFN treatment show little overlap with these transcriptomic datasets.
2020-06-26 | PXD017251 | Pride
Project description:Type III interferon, also known as interferon lambda (IFN-λ), is the newest addition to the IFN family. IFN-λ is primarily produced by the airway epithelium and curbs viral infections without triggering systemic pro-inflammatory cytokine responses1. Of the current IFN COVID-19 trials (as of 6/27/2020), four propose the use of IFN-λ. However, it remains to be determined whether IFN-λ induces ACE2 expression in the human airway epithelium.
2020-12-31 | GSE153428 | GEO
Project description:Whereas most body cells respond to stimulation with type I (alpha and beta) interferon, type III (lambda) interferon was shown to specifically stimulate epithelial cells in the gastrointestinal and respiratory tract. Although both cytokines activate different receptor molecules (IFNAR versus IL-28R/IL-10R, respectively) the downstream signalling pathways and the ultimate response have been reported to be very similar. Here we examined the response of polarized gut intestinal epithelial cells to type I versus type III interferon in order to study potential differences in the transcriptional response.
2017-12-22 | GSE91382 | GEO
Project description:Intestinal epithelial cells (IECs) form a primary barrier against microbial invasion. Prior studies of enteric pathogens have indicated that IEC defense mechanisms are distinct from those of other cell types. For example, antiviral defense of IECs depends on type III interferon whereas most cell types depend on type I IFN. Interferon regulatory factors (IRFs) are a family of transcription factors with well-described roles in stimulation of IFN cytokines, but IRF6 is unique in its preferential expression by epithelial lineages. IRF6 has primarily been studied in epidermal development, but has relatively unknown roles in the intestinal epithelium. Here, we found that Irf6 KO regulated IFN-stimulated antiviral immunity of IECs but had no effect on macrophages. RNseq analysis of Irf6 KO cells showed significant differences in the IFN-stimulated gene expression program that correlated with the magnitude of antiviral gene stimulation. We also found significant baseline phenotypic and transcriptional changes in Irf6 KO IECs, with reduced rate of growth and preturbation of growth and differentiation pathway genes. Knockout of Irf6 in primary IEC organoids also resulted in slower growth and smaller size. Transcriptional analysis of Irf6 KO organoids indicated reduced expression of genes in the epithelial differentiation pathwya, including Wnt and Notch pathway genes, as well as increased expression of a subset of IFN-stimulated genes. These data indicate a previously unappreciated role of Irf6 in shaping the IEC transcriptome, including baseline epithelial development genes and IFN-stimulated genes.
2023-11-01 | GSE245970 | GEO