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Type-I-Interferons induce the decimation of antiviral B cells at the onset of chronic infection [RNA-seq]

ABSTRACT: Abstract: Immune subversion represents a hallmark of persistent infection, but microbial suppression of B cell responses remains mechanistically ill-defined. Adoptive transfer experiments in a chronic viral infection model evidenced the rapid and profound decimation of B cells that responded to virus or to concomitantly administered protein. Decimation affected naïve and memory B cells and resulted from biased differentiation into short-lived antibody-secreting cells. It was driven by type I interferon (IFN-I) signaling to several cell types including dendritic cells, T cells and myeloid cells. Durable B cell responses were restored upon IFN-I receptor blockade or, partially, when depleting myeloid cells or key IFN-I-induced cytokines. B cell decimation represents a molecular mechanism of humoral immune subversion and reflects an unsustainable “all-in” response of B cells in IFN-I-driven inflammation.

ORGANISM(S): Mus musculus

PROVIDER: GSE84037 | GEO | 2016/09/19

SECONDARY ACCESSION(S): PRJNA327853

REPOSITORIES: GEO

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Type-I-Interferons induce the decimation of antiviral B cells at the onset of chronic infection [nanostring]

Project description:Abstract: Immune subversion represents a hallmark of persistent infection, but microbial suppression of B cell responses remains mechanistically ill-defined. Adoptive transfer experiments in a chronic viral infection model evidenced the rapid and profound decimation of B cells that responded to virus or to concomitantly administered protein. Decimation affected naïve and memory B cells and resulted from biased differentiation into short-lived antibody-secreting cells. It was driven by type I interferon (IFN-I) signaling to several cell types including dendritic cells, T cells and myeloid cells. Durable B cell responses were restored upon IFN-I receptor blockade or, partially, when depleting myeloid cells or key IFN-I-induced cytokines.

2016-09-19 | GSE84036 | GEO

Microbial exposure remodels and increases combat readiness of the naïve CD8 T cell compartment via type I interferons

Project description:Studies in specific pathogen-free mice revealed that naïve T (Tn) cells require two homeostatic signals for long-term survival–the sub-threshold T cell receptor:self-peptide–MHC contact, and IL-7 stimulation. It is not known how microbial exposure impacts Tn homeostasis. We report that the presence of infections led to expansion of a novel subpopulation of long-lived, Ly6C+ Tn cells with rapid effector function. Monoinfection with West Nile virus transiently, and polymicrobial exposure persistently, enhanced Ly6C expression on CD5hi cells, the latter yielding a numerical Tn cell increase in the lymph nodes. Conversion and expansion of Ly6C+ Tn cells depended on IFN-I, that upregulated MHC class I expression and enhanced trophic TCR signaling in Tn cells. IFN-I-mediated signals extended lifespan, optimized homing to secondary and tertiary sites, and drove Ly6C+ Tn cells to higher “combat readiness” as judged by increased effector differentiation. Thereby, infection-driven IFN-I powerfully modulates Tn homeostasis and function.

2020-10-07 | GSE159076 | GEO

Type I Interferons Control Proliferation and Function of Intestinal Epithelium

Project description:Wnt pathway-driven proliferation and renewal of the intestinal epithelium must be tightly controlled to prevent development of cancer and barrier dysfunction. Although type 1 interferons (IFN) produced in the gut under influence of microbiota are known for their anti-proliferative effects, the role of these cytokines in regulating intestinal epithelial renewal is largely unknown. Here we report a novel role for IFN in the context of intestinal knockout of casein kinase 1Î± (CK1Î±), which controls ubiquitination and degradation of both Î²-catenin and the IFNAR1 chain of the IFN receptor. Ablation of CK1Î± leads to activation of both Î²-catenin and IFN pathway and prevents unlimited proliferation of intestinal epithelial cells despite constitutive Î²-catenin activity. IFN signaling contributes to activation of the p53 pathway and appearance of apoptotic and senescence markers in the CK1Î±-deficient gut. Concurrent genetic ablation of CK1Î± and IFNAR1 leads to intestinal hyperplasia, robust attenuation of apoptosis, and rapid and lethal loss of the barrier function. These data indicate that IFN plays an important role in controlling proliferation and function of intestinal epithelium in the context of Î²-catenin activation. Two conditions were examined, with 2 replicates for each condition, yielding 4 samples in total.

2016-01-05 | E-GEOD-76512 | biostudies-arrayexpress

Type I interferons govern Zika virus resistance of human macrophages and microglia

Project description:The role of the human type I interferon (IFN-I) system in restricting Zika virus (ZIKV) is uncertain. Here, genetic and pharmacological ablation of IFN-I signalling enhanced ZIKV replication and cytopathicity in macrophages and microglia, key cells in ZIKV transmission and pathogenesis. Thus, despite the extensive IFN-I countermeasures employed by ZIKV, IFN-I dictates the outcome of infection in macrophages. Therapeutic manipulation of the IFN-I system may bring clinical benefit in ZIKV.

2022-10-31 | GSE198542 | GEO

Interferons disrupt lung epithelial repair during recovery from respiratory infection [RN200717]

Project description:Respiratory viral infections cause lung epithelial damage, barrier dysfunction and severe disease. Type I interferons (IFN-a/b) are antiviral cytokines whose therapeutic use is limited by well-characterized pleiotropic effects. Type III IFNs (IFN-λ) are less pro-inflammatory and regarded a superior treatment option. Here, we show that IFN signalling reduces lung epithelial proliferation and differentiation and increases epithelial apoptosis during recovery from viral infection. This delays epithelial repair, increasing disease severity and the risk of bacterial superinfection. IFN-a has least effects, with IFN-b intermediate and IFN-λ strongest action.

2020-06-12 | GSE148710 | GEO

Interferons disrupt lung epithelial repair during recovery from respiratory infection [RN19197]

2020-06-12 | GSE148709 | GEO

Modulation of T cell responses by type I interferons

Project description:Type I interferons (IFNs) play a key role in linking the innate and adaptive immune responses. IFNs can have both positive and negative effects on the development of memory CD8+ T cells, but their contribution to the priming of naÃ¯ve T cells is unclear. Using OT-I TCR transgenic T cells, we show strong effects on TCR-induced functional response when sensitized by IFN-Î² prior to their stimulation with cognate antigen. These effects are only seen in the absence of co-stimulation and at suboptimal TCR stimulation conditions. Pre-stimulation of naÃ¯ve T cells inhibits certain TCR-mediated functions like cell proliferation and the induction of genes such as IFN-Î³ and IL-2. However, type I IFN does not influence the induction of other TCR-induced functions like the expression of the T cell activation marker CD25 and a number of other genes. IFN-mediated impairment of proliferation is due to the lack of IL-2 induction since it can be compensated by exogenous IL-2. Further analysis reveals an IFN-mediated inhibition of Ca2+ flux and ERK phosphorylation. In vivo studies confirm that pre-stimulation with IFNs inhibits early T cell responses, whereas long-term responses are positively affected. Our results reveal that IFN exerts negative effects on naÃ¯ve T cells in a timely defined range under sub-optimal TCR stimulation conditions. These results highlight the importance of timing of immune-regulatory events and reveal a novel role for type I IFNs by shaping the immune response, such that T cells are not able to react until optimal stimulation is provided. 8 Arrays, untreated cells as references, IFNb treatment and/or TCR stimulation at various lengths of time

2015-12-31 | E-GEOD-41381 | biostudies-arrayexpress

Seasonal influenza A virus lineages exhibit divergent abilities to antagonize interferon induction and signaling

Project description:The circulation of seasonal influenza A viruses (IAVs) in humans relies on effective evasion and subversion of the host immune response. While the evolution of seasonal H1N1 and H3N2 viruses to avoid humoral immunity is well characterized, relatively little is known about the evolution of innate immune antagonism phenotypes in these viruses. Numerous studies have established that only a small subset of infected cells are responsible for initiating the type I and type III interferon (IFN) response during IAV infection, emphasizing the importance of single cell studies to accurately characterize the IFN response during infection. We developed a flow cytometry-based method to examine transcriptional changes in IFN and interferon stimulated gene (ISG) expression at the single cell level. We observed that NS segments derived from seasonal H3N2 viruses are more efficient at antagonizing IFN signaling but less effective at suppressing IFN induction, compared to the pdm2009 H1N1 lineage. We compared a collection of NS segments spanning the natural history of the current seasonal IAV lineages, and demonstrate long periods of stability in IFN antagonism potential, punctuated by occasional phenotypic shifts. Altogether, our data reveal significant differences in how seasonal and pandemic H1N1 and H3N2 viruses antagonize the human IFN response at the single cell level.

2024-07-12 | GSE272070 | GEO

Type I Interferons Control Proliferation and Function of Intestinal Epithelium

Project description:Wnt pathway-driven proliferation and renewal of the intestinal epithelium must be tightly controlled to prevent development of cancer and barrier dysfunction. Although type 1 interferons (IFN) produced in the gut under influence of microbiota are known for their anti-proliferative effects, the role of these cytokines in regulating intestinal epithelial renewal is largely unknown. Here we report a novel role for IFN in the context of intestinal knockout of casein kinase 1α (CK1α), which controls ubiquitination and degradation of both β-catenin and the IFNAR1 chain of the IFN receptor. Ablation of CK1α leads to activation of both β-catenin and IFN pathway and prevents unlimited proliferation of intestinal epithelial cells despite constitutive β-catenin activity. IFN signaling contributes to activation of the p53 pathway and appearance of apoptotic and senescence markers in the CK1α-deficient gut. Concurrent genetic ablation of CK1α and IFNAR1 leads to intestinal hyperplasia, robust attenuation of apoptosis, and rapid and lethal loss of the barrier function. These data indicate that IFN plays an important role in controlling proliferation and function of intestinal epithelium in the context of β-catenin activation.

2016-01-05 | GSE76512 | GEO

Transcription profiling of human endothelial and fibroblast cells isolated from umbilical cord veins treated with interferons to identify genes regulated by interferons

Project description:IFNs are highly pleiotropic cytokines also endowed with marked anti-angiogenic activity. In this study, the mRNA expression profiles of endothelial cells (EC) exposed in vitro to IFN-alpha, IFN-beta, or; IFN-gamma were determined. We found that in HUVEC as well as in other EC types 175 genes were upregulated (>2-fold increase) by IFNs, including genes involved in the host response to RNA viruses, inflammation, and apoptosis. Interestingly, 41 genes showed a >5-fold higher induction by IFN-alpha in EC compared to human fibroblasts; among them, the gene encoding the angiostatic chemokine CXCL11 was selectively induced by IFN-alpha in EC along with other genes associated; with angiogenesis regulation, including CXCL10, TRAIL, and guanylate binding protein 1 (GBP-1). These transcriptional changes were confirmed and extended by quantitative PCR analysis and ELISA; whereas IFN-alpha and IFN-beta exerted virtually identical effects on transcriptome modulation, a differential gene regulation by type I and type II IFN emerged, especially as far as quantitative aspects were concerned. In vivo, IFN-alpha-producing tumors over-expressed murine CXCL10-11,; GBP-1 and TRAIL, with evidence of CXCL11 production by tumor-associated EC. Overall, these findings improve our understanding of the anti-angiogenic effects of IFNs by showing that these cytokines trigger an anti-angiogenic transcriptional program in EC. Moreover, we suggest that quantitative differences in the magnitude of the transcriptional activation of IFNresponsive genes could form the basis for cell-specific transcriptional signatures. In press, J. Immunol. 2007. Experiment Overall Design: comparison of interferon effects on endothelial cells (HUVEC, HMVEC) and fibrobloasts

2009-04-08 | E-GEOD-3920 | biostudies-arrayexpress

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