Ontology highlight
ABSTRACT:
PROVIDER: PRJNA542116 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9034680_1.fastq.gz | Fastqsanger.gz | |||
| SRR9034680_2.fastq.gz | Fastqsanger.gz | |||
| SRR9034681_1.fastq.gz | Fastqsanger.gz | |||
| SRR9034681_2.fastq.gz | Fastqsanger.gz | |||
| SRR9034679_1.fastq.gz | Fastqsanger.gz |
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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: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.
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Project description:Inborn errors of human IFN-γ immunity underlie mycobacterial diseases, while 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. They have no history of severe viral disease, despite exposure to many viruses, including SARS-CoV-2 that is life-threatening in individuals with deficient IFN-a/b. There is a much greater IRF1-dependent response to IFN-γ than IFN-a/b in vitro, both quantitatively and qualitatively. Monocyte-derived macrophages and iPSC-derived macrophages of both patients do not upregulate at least 40% of target genes normally induced by IFN-γ. In contrast, cell-intrinsic IFN-a/b immunity to a wide range of viruses, including HIV and SARS-CoV-2, is maintained. Human IRF1 is thus largely redundant for antiviral IFN-a/b immunity across cell types. By contrast, human IRF1 is essential for IFN-γ immunity to mycobacteria in mononuclear myeloid cells.
2023-01-12 | GSE216488 | GEO
Project description:Inborn errors of human IFN-γ immunity underlie mycobacterial diseases, while 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. They have no history of severe viral disease, despite exposure to many viruses, including SARS-CoV-2 that is life-threatening in individuals with deficient IFN-a/b. There is a much greater IRF1-dependent response to IFN-γ than IFN-a/b in vitro, both quantitatively and qualitatively. Monocyte-derived macrophages and iPSC-derived macrophages of both patients do not upregulate at least 40% of target genes normally induced by IFN-γ. In contrast, cell-intrinsic IFN-a/b immunity to a wide range of viruses, including HIV and SARS-CoV-2, is maintained. Human IRF1 is thus largely redundant for antiviral IFN-a/b immunity across cell types. By contrast, human IRF1 is essential for IFN-γ immunity to mycobacteria in mononuclear myeloid cells.
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Project description:Inborn errors of immunity (IEI) result in increased morbidity and mortality from infections. However, discovering new IEIs is limited by the clinical identification of rare patient cohorts. To predict immunodeficiency-associated genes in a patient-independent approach, we performed a targeted CRISPR-Cas9 knockout screen in healthy human donor-derived PBMCs and identified myocyte enhancer factor 2C (MEF2C) as essential for primary human natural killer (NK) cell functionality ex vivo. MEF2C haploinsufficient (MCHS) patients and mice displayed impaired NK cell development, ex vivo function, and increased susceptibility to viral infection. MEF2C was required for cytokine-induced changes in NK cell metabolism and SREBP-mediated lipid homeostasis, and oleic acid supplementation restored MCHS patient NK cell cytotoxic function. Thus, we demonstrate a CRISPR-based methodology in primary human immune cells to accelerate the identification of new IEIs, and apply this approach to predict and validate a new NK cell immunodeficiency associated with metabolic and functional defects.
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Project description:Type I interferons (IFN-I) exert pleiotropic biological effects during viral infections, balancing virus control versus immune-mediated pathologies and have been successfully employed for the treatment of viral diseases. Humans express twelve IFN-alpha (α) subtypes, which activate downstream signalling cascades and result in distinct patterns of immune responses and differential antiviral responses. Inborn errors in type I IFN immunity and the presence of anti- IFN autoantibodies account for very severe courses of COVID-19, therefore, early administration of type I IFNs may be protective against life-threatening disease. Here we comprehensively analysed the antiviral activity of all IFNα subtypes against SARS-CoV-2 to identify the underlying immune signatures and explore their therapeutic potential. Prophylaxis of primary human airway epithelial cells (hAEC) with different IFNα subtypes during SARS-CoV-2 infection uncovered distinct functional classes with high, intermediate and low antiviral IFNs. In particular IFNα5 showed superior antiviral activity against SARS-CoV-2 infection. Dose-dependency studies further displayed additive effects upon co-administered with the broad antiviral drug remdesivir in cell culture. Transcriptomics of IFN-treated hAEC revealed different transcriptional signatures, uncovering distinct, intersecting and prototypical genes of individual IFNα subtypes. Global proteomic analyses systematically assessed the abundance of specific antiviral key effector molecules which are involved in type I IFN signalling pathways, negative regulation of viral processes and immune effector processes for the potent antiviral IFNα5. Taken together, our data provide a systemic, multi-modular definition of antiviral host responses mediated by defined type I IFNs. This knowledge shall support the development of novel therapeutic approaches against SARS-CoV-2.
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Project description:Various inborn errors of the canonical NF-kB pathway underlie different forms of human immunodeficiency. However, no patients with autosomal recessive complete deficiencies of RelA, c-REL, or NF-kB1, the three core members of the canonical NF-kB pathway, have yet been identified. We report a child homozygous for a loss-of-expression mutation of REL, encoding c-REL, which is expressed principally in myeloid and lymphoid cells. The distribution of myeloid subsets is normal in this patient, but in vitro-derived monocytes and cDC1s, unlike cDC2s, have impaired IL-12 and IL-23 production. The patient has low frequencies of memory CD4+ T cells, Th1*, Th2, Tregs, and almost no memory B cells. The frequencies of the other lymphoid subsets are normal. The patient’s naïve and memory CD4+ T cells produce only small amounts of IL-2, and the addition of this interleukin rescues their proliferation in response to mitogens, but not to antigens, in vitro. However, we found that HLA-syngeneic control cDCs rescued the proliferation of these cells in response to recall antigens. The production of key effector cytokines, such as IL-4, IL-17A, and IFNg, by memory CD4+ T cells was also highly impaired ex vivo, as was the differentiation of naïve CD4+ T cells into Th1 and Th17 cells in vitro. Both the survival and proliferation of the patient’s naïve B cells were found to be compromised, preventing B-cell differentiation into immunoglobulin (Ig)-secreting plasmablasts in vitro. As a consequence of this pleiotropic effect, this child suffered from severe viral, mycobacterial, fungal, and parasitic infections, while IgG substitution treatment prevented pyogenic infections. The immunological and infectious phenotypes were of hematopoietic origin, as they were cured by hematopoietic stem cell transplantation. Inherited human c-REL deficiency impairs multiple core functions of DCs, T cells, and B cells, thereby disrupting adaptive immunity to multiple infections.
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