Intrinsic OASL expression licenses interferon induction during influenza A virus infection

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 17, 2025

Effective control of viral infection requires rapid induction the innate immune response, especially type I and III interferon (IFN) systems. Despite critical role IFN in host defense, numerous studies have established that most cells fail to produce IFNs response stimuli. The specific factors govern cellular heterogeneity potential during are not understood. To identify license some but others mount an infection, we developed approach for analyzing temporal scRNA-seq data influenza A virus (IAV)-infected cells. This identified expression several stimulated genes (ISGs) within pre-infection as correlates those cells, post-infection. Validation experiments confirmed intrinsic ISG OASL is essential robust IFNL IAV infection. Altogether, our findings reveal important IFN-independent, ISGs promoting provide new insights into mechanisms regulate cell-to-cell activation.

Language: Английский

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Type I interferon autoantibody footprints reveal neutralizing mechanisms and allow inhibitory decoy design

The Journal of Experimental Medicine, Journal Year: 2025, Volume and Issue: 222(6)

Published: March 20, 2025

Autoantibodies neutralizing type I interferons (IFN-Is; IFNα or IFNω) exacerbate severe viral disease, but specific treatments are unavailable. With footprint profiling, we delineate two dominant IFN-I faces commonly recognized by autoantibody–containing plasmas from aged individuals with HIV-1 and COVID-19. These overlap regions independently essential for engaging the IFNAR1/IFNAR2 heterodimer, efficiently block interaction of both receptor subunits in vitro. In contrast, non-neutralizing limit only one subunit display relatively low IFN-I–binding avidities, thus likely hindering function. Iterative engineering signaling-inert mutant IFN-Is (simIFN-Is) retaining autoantibody targets created potent decoys that prevent neutralization autoantibody-containing restore IFN-I–mediated antiviral activity. Additionally, microparticle-coupled simIFN-Is were effective at depleting autoantibodies plasmas, leaving antibodies unaffected. Our study reveals mechanisms action demonstrates a proof-of-concept strategy to alleviate pathogenic effects.

Language: Английский

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DOCK2 Deficiency and GATA2 Haploinsufficiency Can Underlie Critical Coronavirus Disease 2019 (COVID-19) Pneumonia

Journal of Clinical Immunology, Journal Year: 2025, Volume and Issue: 45(1)

Published: March 28, 2025

Language: Английский

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Sterile production of interferons in the thymus

The Journal of Immunology, Journal Year: 2025, Volume and Issue: unknown

Published: April 4, 2025

Abstract T-cell central tolerance is controlled by thymocyte TCR recognition of self-peptides presented thymic APCs. While epithelial cells are essential for tolerance, a variety other traditional APCs also play critical roles in selection. Similar to how peripheral require activation become effective, tolerogenic. Recent studies have identified IFNs as an factor the and generation optimally tolerogenic environment. In this review, we focus on interferon (IFN) production within thymus its effects developing thymocytes. We examine importance IFN itself well interferon-stimulated proteins generated during immune responses.

Language: Английский

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Anti-cytokine autoantibodies in human susceptibility to infectious diseases: insights from Inborn errors of immunity

Immunological Medicine, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 17

Published: April 8, 2025

The study of Inborn Errors Immunity (IEIs) is critical for understanding the complex mechanisms human immune response to infectious diseases. Specific IEIs, characterized by selective susceptibility certain pathogens, have enhanced our key molecular pathways and cellular subsets involved in host defense against pathogens. These insights revealed that patients with anti-cytokine autoantibodies exhibit phenotypes similar those pathogenic mutations genes encoding signaling molecules. This new disease concept currently categorized as 'Phenocopies IEI'. category includes targeting IL-17/IL-22, IFN-γ, IL-6, GM-CSF, type I IFNs. Abundant deplete corresponding cytokines, impair pathways, increase specific We herein demonstrate clinical etiological significance immunity Insights from studies rare IEIs underscore pathological importance cytokine-targeting autoantibodies. Simultaneously, diverse phenotype these suggests influences cytokine dysfunction are broader than previously recognized. Furthermore, comprehensive prompted COVID-19 pandemic highlighted substantial impact their potential role shaping outcomes disease.

Language: Английский

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ATP functions as a pathogen-associated molecular pattern to activate the E3 ubiquitin ligase RNF213

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: May 13, 2025

Language: Английский

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Ruxolitinib Rescues Multiorgan Clinical Autoimmunity in Patients with APS-1

Journal of Clinical Immunology, Journal Year: 2023, Volume and Issue: 44(1)

Published: Dec. 19, 2023

Autoimmune polyendocrine syndrome type-1 (APS-1) is caused by mono- or biallelic loss-of-function variants of the autoimmune regulator gene AIRE underlying early-onset multiorgan autoimmunity and production neutralizing autoantibodies against cytokines, accounting for mucosal candidiasis viral diseases. Medical intervention essential to prevent attenuate manifestations. Ruxolitinib a JAK inhibitor approved use in several conditions. It also used off-label treat manifestations growing range inborn errors immunity. We treated three APS-1 patients with ruxolitinib followed them at least 30 months. Tolerance was excellent, no medical biological adverse events. All had remarkably positive responses alopecia, nail dystrophy, keratitis, candidiasis, steroid-dependent hepatitis, exocrine pancreatic insufficiency, renal potassium wasting, hypoparathyroidism, diabetes insipidus. inhibitors were therefore considered an effective treatment APS-1. Our observations suggest that JAK/STAT pathways are involved pathogenesis They should be tested broader patients.

Language: Английский

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Suppression of Type I Interferon Signaling in Myeloid Cells by Autoantibodies in Severe COVID-19 Patients

Journal of Clinical Immunology, Journal Year: 2024, Volume and Issue: 44(4)

Published: April 22, 2024

Abstract Purpose Auto-antibodies (auto-abs) to type I interferons (IFNs) have been identified in patients with life-threatening coronavirus disease 2019 (COVID-19), suggesting that the presence of auto-abs may be a risk factor for severity. We therefore investigated mechanism underlying COVID-19 exacerbation induced by IFNs. Methods evaluated plasma from 123 measure performed single-cell RNA sequencing (scRNA-seq) peripheral blood mononuclear cells and conducted epitope mapping auto-abs. Results Three 19 severe 4 42 critical had neutralizing Patients IFNs showed no characteristic clinical features. scRNA-seq 38 revealed IFN signaling conventional dendritic canonical monocytes was attenuated, SARS-CoV-2-specific BCR repertoires were decreased Furthermore, IFN-α2 recognized epitopes IFN-α2, which binds receptor. Conclusion Auto-abs found inhibited blocking binding its The failure properly induce production an antibody SARS-CoV-2 causative

Language: Английский

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The zebrafish as a potential model for vaccine and adjuvant development

Expert Review of Vaccines, Journal Year: 2024, Volume and Issue: 23(1), P. 535 - 545

Published: April 26, 2024

Zebrafishes represent a proven model for human diseases and systems biology, exhibiting physiological genetic similarities having innate adaptive immune systems. However, they are underexplored vaccinology, vaccine development, testing. Here we summarize gaps challenges.

Language: Английский

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Yin and yang of interferons: lessons from the coronavirus disease 2019 (COVID-19) pandemic

Current Opinion in Immunology, Journal Year: 2024, Volume and Issue: 87, P. 102423 - 102423

Published: April 1, 2024

Language: Английский

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