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Microarray analysis of IFN-response

ABSTRACT: Type I interferon (IFN-α/β) is the first line of defense against viral infection. Mouse models have been pivotal to our understanding of IFN-α/β in immunity, although validation of these findings in humans has not been possible. We investigated a previously healthy child with fatal susceptibility to the live-attenuated measles, mumps and rubella (MMR) vaccine. By targeted resequencing we identified a homozygous mutation in the high-affinity interferon-α/β receptor (IFNAR2), which rendered cells unresponsive to IFN-α/β and led to unrestricted replication of IFN-attenuated viruses. Reconstitution of patient cells with wild-type IFNAR2 restored IFN-α/β responsiveness and viral resistance. Despite the failure to control vaccine viruses, the patient showed no evidence of susceptibility to conventional viral pathogens in vivo and adaptive immunity appeared normal. Human IFNAR2 deficiency therefore reveals an essential role for IFN-α/β in resistance to attenuated viruses, but significant and unexpected redundancy overall in antiviral immunity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE67737 | GEO | 2015/06/12

SECONDARY ACCESSION(S): PRJNA280773

REPOSITORIES: GEO

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Microarray analysis of IFN-response

Project description:Type I interferon (IFN-α/β) is the first line of defense against viral infection. Mouse models have been pivotal to our understanding of IFN-α/β in immunity, although validation of these findings in humans has not been possible. We investigated a previously healthy child with fatal susceptibility to the live-attenuated measles, mumps and rubella (MMR) vaccine. By targeted resequencing we identified a homozygous mutation in the high-affinity interferon-α/β receptor (IFNAR2), which rendered cells unresponsive to IFN-α/β and led to unrestricted replication of IFN-attenuated viruses. Reconstitution of patient cells with wild-type IFNAR2 restored IFN-α/β responsiveness and viral resistance. Despite the failure to control vaccine viruses, the patient showed no evidence of susceptibility to conventional viral pathogens in vivo and adaptive immunity appeared normal. Human IFNAR2 deficiency therefore reveals an essential role for IFN-α/β in resistance to attenuated viruses, but significant and unexpected redundancy overall in antiviral immunity. Total RNA isolated from IFNAR2-deficient patient (in triplicate) and control (three independent control lines) fibroblasts treated with IFNalpha, IFNbeta or IFNgamma (1000 IU/mL) for 10h

2015-06-12 | E-GEOD-67737 | biostudies-arrayexpress

Human IRF1 governs macrophagic IFN-γ immunity to mycobacteria

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

Herpes simplex encephalitis in a patient with a new form of inherited IFNAR1 deficiency

Project description:Inborn errors of TLR3-dependent IFN-α/β- and -λ-mediated immunity in the central nervous system (CNS) can underlie herpes simplex virus 1 (HSV-1) encephalitis (HSE). The respective contributions of IFN-α/β- and -λ are unknown. We report a child homozygous for a genomic deletion of the entire coding sequence and part of the 3’UTR of the last exon of IFNAR1, who died from HSE at the age of two years. An older cousin died following vaccination against measles, mumps and rubella at 12 months of age, and another 17-year-old cousin homozygous for the same variant has had other viral illnesses. The encoded IFNAR1 protein is expressed on the cell surface but is truncated and cannot interact with the tyrosine kinase TYK2. The patient’s fibroblasts and EBV-B cells did not respond to IFN-α2b or IFN-β, in terms of STAT1, STAT2 and STAT3 phosphorylation, or the induction of IFN-stimulated genes (ISGs). Transcriptome analysis revealed a complete abolition of genome-wide ISG induction in response to IFN-α2b in IFNAR1-deficient fibroblasts from the patient. These fibroblasts were susceptible to viruses, including HSV-1, even in the presence of exogenous IFN-α2b or IFN-β. HSE is therefore a consequence of inherited complete IFNAR1 deficiency. This experiment of Nature indicates that IFN-α/β are essential for anti-HSV-1 immunity in the CNS.

2020-09-24 | GSE157948 | GEO

TLR-mediated type I IFN induction in pDCs requires the rapamycin-sensitive PI3K-mTOR-p70S6K pathway

Project description:Robust type I interferon (IFN-alpha/beta) production in plasmacytoid dendritic cells (pDCs) is critical for anti-viral immunity. Here we demonstrated a role for the mammalian target of rapamycin (mTOR) pathway in regulating interferon production by pDCs. Inhibition of mTOR or the ‘downstream’ mediators of mTOR p70S6K1,2 kinases during pDC activation via Toll-like receptor 9 (TLR9) blocked the interaction of TLR9 with the adaptor MyD88 and the subsequent activation of interferon response factor 7 (IRF7), resulting in impaired IFN-alpha production. Microarray analysis confirmed that inhibition of mTOR by the immunosuppressive drug rapamycin suppressed anti-viral and anti-inflammatory gene expression. Consistent with this, targeting rapamycin-encapsulated microparticles to antigen-presenting cells in vivo resulted in a diminution of IFN-alpha production in response to CpG DNA or the yellow fever vaccine virus strain 17D. Thus, mTOR signaling plays a critical role in TLR-mediated IFN-alpha responses by pDCs. CpGA is a TLR9 agonist. pDCs were isolated from mouse spleen or human PBMC. The effect of rapamycin on pDCs IFN-alpha production as induced by TLR ligands was studied. The mechanism of rapamycin effect was dissected in RAW cell line.

2008-12-01 | E-GEOD-12218 | biostudies-arrayexpress

Repurposing Live Attenuated Trivalent MMR Vaccine as Cost-effective Cancer ImmunotherapyRepurposing Live Attenuated Trivalent MMR Vaccine as Cost-effective Cancer Immunotherapy

Project description:In this study, we show that intratumoral injections of the trivalent measles, mumps, and rubella (MMR) live attenuated viral vaccine (LAVs) modulate a potent cytotoxic T cells immune response, resulting in tumor growth inhibition and improved survival in syngeneic mouse models of hepatocellular carcinoma (HCC) and colorectal cancer (CRC).

2022-10-27 | PXD031295 | Pride

Affect of antiviral ribavirin on YFV WT and vaccine strains.

Project description:Live-attenuated viral vaccines have been successfully used to combat infectious disease for decades but due to their empirical derivation, little is known about their mechanisms of attenuation. This lack of understanding makes the development of next generation live attenuated vaccines difficult. The success of the 17D vaccine and availability of the parent virus, Asibi, makes it an excellent model to understand the molecular basis of attenuation of a live attenuated vaccine and the effects of viral diversity on vaccine function. Due to the differences in genetic diversity between WT Asibi virus and its 17D vaccine derivative, we investigated the changes in genetic diversity of 17D and Asibi viruses following treatment with ribavirin.

2020-01-01 | E-MTAB-8504 | biostudies-arrayexpress

Synthetic mimetics assigned a major role to IFNAR2 in type I Interferon signaling

Project description:Type I Interferons (IFNs) are potent inhibitors of viral replication. Here, we reformatted the natural murine and human type I Interferon-α/β receptors IFNAR1 and IFNAR2 into fully synthetic biological switches. The transmembrane and intracellular domains of natural IFNAR1 and IFNAR2 were conserved, whereas the extracellular domains were exchanged by nanobodies directed against the fluorescent proteins Green fluorescent protein (GFP) and mCherry. Using this approach, multimeric single-binding GFP-mCherry ligands induced synthetic IFNAR1/IFNAR2 receptor complexes and initiated STAT1/2 mediated signal transduction via Jak1 and Tyk2. Homodimeric GFP and mCherry ligands showed that IFNAR2 but not IFNAR1 homodimers were sufficient to induce sustained STAT1/2 signaling. Transcriptome analysis revealed that synthetic murine type I IFN signaling was highly comparable to IFNα4 signaling and resulted in efficient elimination of vesicular stomatitis virus (VSV) in a cell culture based viral infection model using MC57 cells stimulated with synthetic type IFN ligands. Using intracellular deletion variants and point mutations, Y510 and Y335 in murine IFNAR2 were verified as unique phosphorylation sites for STAT1/2 activation, whereas the other tyrosine residues in IFNAR1 and IFNAR2 were not involved in STAT1/2 phosphorylation. Comparative analysis of synthetic human IFNARs supporting this finding. In summary, our data showed that synthetic type I IFN signal transduction is originating from IFNAR2 rather than IFNAR1.

2022-09-21 | GSE202839 | GEO

TLR-mediated type I IFN induction in pDCs requires the rapamycin-sensitive PI3K-mTOR-p70S6K pathway

2008-12-01 | GSE12218 | GEO

IRF1 mass-spectrometry primary fibroblasts non-stimulated or stimulated with IFNg for 24h

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

Herpes simplex host shutoff attenuates antiviral state

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

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