Type-I-Interferons induce the decimation of antiviral B cells at the onset of chronic infection [nanostring]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE84036 | GEO | 2016/09/19
SECONDARY ACCESSION(S): PRJNA327852
REPOSITORIES: GEO
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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. 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.
2016-09-19 | GSE84037 | GEO
Project description:Background: The olfactory epithelium (OE) is one of the few sites where environmental pathogens can gain direct access to the brain. Despite this vulnerable arrangement, little is known about the protective mechanisms in the OE to prevent viral infection and subsequent entry into the brain. Methods: We systematically investigated acute responses in the olfactory mucosa (OM) upon exposure to vesicular stomatitis virus (VSV) by RNA-seq. VSVs were nasally inoculated into C57BL/6 mice. OM were dissected for gene expression analysis at different time points after viral inoculation. Interferon functions were determined by comparing viral gene expression in interferon (Ifn) receptor knockout (Ifnar1-/- and Ifnlr1-/-) with wildtype OM. Results: Antiviral responses were observed as early as 24hrs post viral exposure in the OM. Amongst the rapidly upregulated transcripts observed were specific type I as well as type III Ifns and interferon stimulated genes. Genetic analyses demonstrated that both type I and type III IFN signaling are required for the suppression of viral replication in the OM. Nasal IFNb1 or IFNl2 administration effectively reduces viral load in the OM. Conclusions: OE possesses innate ability to respond and suppress viral infection. Type I and type III IFNs actively participate in the OE’s antiviral functions. Nasal IFN application effectively blocks viral replication in the OE suggesting therapeutic potential against viral insult.
2023-07-03 | GSE154235 | GEO
Project description:Herpes simplex virus mutants lacking the vhs gene are severely attenuated in animal models of pathogenesis and exhibit reduced growth in primary cell culture. As a result of these properties vhs-deleted virus have been proposed as live-attenuated viruses. Despite these findings and their implications for vacccines, the mechanisms by which vhs promotes infection in cell culture and in vivo are not understood. In this study we demonstrate that vhs-deficent viruses replicate to reduced levels in interferon(IFN)- primed cells. Furthermore, vhs-defective viruses induce increased levels of IFN? and IFN?-stimulated genes, and increased levels of eIF2? phosphorylation in infected cells. In addition, we demonstrate a generalized over-expression of viral RNAs following infection with a vhs-deficient virus. This suggests increased expression of IFN pathway inducing double stranded RNA, a potent pathogen-associated molecular pattern (PAMP). Together these data show that vhs likely functions to reduce innate immune responses and thereby acts as critical determinant of viral pathogenesis. Keywords: time course, genetic modification Time course (1,3,6,9 & 12h) of HSV infected mouse embryo fibroblasts. Wild type (KOS) virus is co-hybridized with vhs null virus (NHB). Each time-point is hybridized in quadruplicate.
2008-04-03 | E-GEOD-10962 | biostudies-arrayexpress
Project description:The majority of SARS-CoV-2 infections among healthy individuals result in asymptomatic to mild disease. However, the immunological mechanisms defining effective lung tissue protection from SARS-CoV-2 infection remain elusive. Unlike mice solely engrafted with human fetal lung xenograft (fLX), mice co-engrafted with fLX and a myeloid-enhanced human immune system (HNFL mice) are resistant to SARS-CoV-2 infection, severe inflammation, and histopathology. Effective control of viral infection in HNFL mice associated with significant macrophage infiltration, and the induction of a potent macrophage-mediated interferon response. The strong upregulation of the USP18-ISG15 axis, a negative regulator of IFN responses, by macrophages was unique to HNFL mice and represented a prominent correlate of reduced inflammation and histopathology. Altogether, our work shed lights on unique cellular and molecular correlate of lung tissue protection during SARS-CoV-2 infection, and underscores macrophage IFN responses as prime targets for developing immunotherapies against coronavirus respiratory diseases.
2022-04-19 | GSE180063 | GEO
Project description:The majority of SARS-CoV-2 infections among healthy individuals result in asymptomatic to mild disease. However, the immunological mechanisms defining effective lung tissue protection from SARS-CoV-2 infection remain elusive. Unlike mice solely engrafted with human fetal lung xenograft (fLX), mice co-engrafted with fLX and a myeloid-enhanced human immune system (HNFL mice) are resistant to SARS-CoV-2 infection, severe inflammation, and histopathology. Effective control of viral infection in HNFL mice associated with significant macrophage infiltration, and the induction of a potent macrophage-mediated interferon response. The strong upregulation of the USP18-ISG15 axis, a negative regulator of IFN responses, by macrophages was unique to HNFL mice and represented a prominent correlate of reduced inflammation and histopathology. Altogether, our work shed lights on unique cellular and molecular correlate of lung tissue protection during SARS-CoV-2 infection, and underscores macrophage IFN responses as prime targets for developing immunotherapies against coronavirus respiratory diseases.
2022-04-19 | GSE180908 | GEO
Project description:Activation of interferon-stimulated gene (ISG) responses is critical for control of viral infection. We recently identified that stimulation of the NLRP3 inflammasome and mobilization of the inflammatory cytokine IL-1β act as critical host restrictive pathways against West Nile virus (WNV) in a mechanism dependent on the regulation of ISGs. In order to define the mechanism by which IL-1β regulates these antiviral immune programs, we utilized global transcriptome analysis in myeloid cells, known targets of WNV replication to define gene signatures required for IL-1β driven antiviral responses. Surprisingly, we found IL-1β dependent activation of interferon-beta (IFN-β) and ISGs at late times following IL-1β treatment. Expression of these antiviral innate immune genes was found to be dependent on activation of IRF3 and appears to reflect a general shift in IL-1β signaling from an inflammatory response early following treatment to an anti-inflammatory type-I IFN mediated response at later times post-treatment. These data demonstrate that inflammatory and antiviral signals integrate to control viral infection. Strategies to co-opt these cytokine activated antiviral signatures can act as novel targeted therapeutic strategies tailored specifically to individual pathogens.
2018-01-12 | GSE109069 | GEO
Project description:Patients with high-risk non-muscle-invasive bladder cancer (NMIBC) frequently relapse after standard intravesical BCG therapy and may have a dismal outcome. Resistance mechanisms to such immunotherapy remain misunderstood. Here, using cancer cell lines, freshly resected human bladder tumors and cohorts of bladder cancer patients pre- and post-BCG therapy, we demonstrate two distinct patterns of immune subversion upon BCG relapse. In the first pattern, intracellular BCG infection of cancer cells induced a post-transcriptional downregulation of HLA-I membrane expression via an inhibition of the autophagy flux. Patients with HLA-I deficient cancer cells post-BCG therapy displayed a myeloid immunosuppressive tumor microenvironment with epithelial-to-mesenchymal transition (EMT) characteristics and dismal outcomes. Conversely, patients with HLA-I proficient cancer cells post-BCG therapy presented with CD8+ T cell tumor infiltrates, upregulation of inflammatory cytokines and inhibitory immune checkpoint molecules. Those patients had a very favorable outcome. We surmise that HLA-I expression in bladder cancers at relapse post-BCG does not result from immunoediting but rather from an immune subversion process directly induced by BCG on cancer cells, which predicts dismal prognosis. Cancer cells HLA-I scoring by immunohistochemistry (IHC) staining can be easily implemented by pathologists in routine practice to stratify future urothelial cancer patient treatment strategies.
2022-05-05 | GSE199617 | GEO
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 naïve T cells is unclear. Using OT-I TCR transgenic T cells, we show strong effects on TCR-induced functional response when sensitized by IFN-β 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 naïve T cells inhibits certain TCR-mediated functions like cell proliferation and the induction of genes such as IFN-γ 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 naïve 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
Project description:Transcriptional response to virus infection in mice lacking type I and type III signaling The transcriptional response to virus infection is thought to be predominantly induced by interferon (IFN) signaling. Here we demonstrate that, in the absence of IFN signaling, an IFN-like transcriptome is still maintained. This transcriptional activity is mediated from IFN-stimulated response elements (ISREs) that bind to both the IFN stimulated gene factor 3 (ISGF3) as well as to IFN response factor 7 (IRF7). Through a combination of both in vitro biochemistry and in vivo transcriptional profiling, we have dissected what constitutes IRF-specific, ISGF3-specific, or universal ISREs. Taken together, the data presented here suggests that IRF7 can induce an IFN-like transcriptome in the absence of type-I or -III signaling and therefore provides a level of redundancy to cells to ensure the induction of the antiviral state. Mouse: Infections were performed in triplicate and lungs from each condition were pooled for total RNA isolation. Human: Analysis of IRF7 transcriptome in U3A cell line was performed in duplicates.
2010-10-15 | E-GEOD-24695 | biostudies-arrayexpress
Project description:Transcription factor IRF3 is critical for the induction of antiviral type I interferon (IFN-I). The epigenetic regulation of IFN-I production in antiviral innate immunity need to be further identified. Here, we report that epigenetic remodeler ARID1A, a critical component of the mSWI/SNF complex, could bind IRF3 and then was recruited to the Ifn-I promoter by IRF3, thus selectively promoting IFN-I but not TNF-α, IL-6 production in macrophages upon viral infection. Myeloid cell-specific deficiency of Arid1a rendered mice more susceptible to viral infection, accompanied with less IFN-I production. Mechanistically, ARID1A facilitates chromatin accessibility of IRF3 at the Ifn-I promoter by interacting with histone methyltransferase NSD2, which methylates H3K4 and H3K36 of promoter region. Our findings demonstrate the new roles of ARID1A and NSD2 in innate immunity, providing insight to the crosstalks of chromatin remodeling, histone modification and transcription factor in the epigenetic regulation of antiviral innate immunity.
2022-07-01 | GSE176452 | GEO