Loss of GM-CSF-dependent instruction of alveolar macrophages in COVID-19 provides a rationale for inhaled GM-CSF treatment DOI Creative Commons
Cédric Bosteels, Karel Van Damme, Elisabeth De Leeuw

et al.

Cell Reports Medicine, Journal Year: 2022, Volume and Issue: 3(12), P. 100833 - 100833

Published: Nov. 16, 2022

GM-CSF promotes myelopoiesis and inflammation, blockade is being evaluated as a treatment for COVID-19-associated hyperinflammation. Alveolar is, however, required monocytes to differentiate into alveolar macrophages (AMs) that control homeostasis. By mapping cross-species AM development clinical lung samples, we discovered COVID-19 marked by defective GM-CSF-dependent instruction accumulation of pro-inflammatory macrophages. In multi-center, open-label RCT in 81 non-ventilated patients with respiratory failure, found inhalation rhu-GM-CSF did not improve mean oxygenation parameters compared standard treatment. However, more on had response, induced higher numbers virus-specific CD8 effector lymphocytes class-switched B cells, without exacerbating systemic This translational proof-of-concept study provides rationale further testing inhaled non-invasive gas exchange simultaneously boost antiviral immunity COVID-19. registered at ClinicalTrials.gov (NCT04326920) EudraCT (2020-001254-22).

Language: Английский

Cross-tissue immune cell analysis reveals tissue-specific features in humans DOI Creative Commons
Cecilia Domínguez Conde, Chuan Xu, Lorna B. Jarvis

et al.

Science, Journal Year: 2022, Volume and Issue: 376(6594)

Published: May 12, 2022

Despite their crucial role in health and disease, our knowledge of immune cells within human tissues remains limited. We surveyed the compartment 16 from 12 adult donors by single-cell RNA sequencing VDJ generating a dataset ~360,000 cells. To systematically resolve cell heterogeneity across tissues, we developed CellTypist, machine learning tool for rapid precise type annotation. Using this approach, combined with detailed curation, determined tissue distribution finely phenotyped types, revealing hitherto unappreciated tissue-specific features clonal architecture T B Our multitissue approach lays foundation identifying highly resolved types leveraging common reference dataset, tissue-integrated expression analysis, antigen receptor sequencing.

Language: Английский

Citations

589
The IL-1β, IL-6, and TNF cytokine triad is associated with post-acute sequelae of COVID-19 DOI
Christoph Schultheiß, Edith Willscher, Lisa Paschold

et al.

Cell Reports Medicine, Journal Year: 2022, Volume and Issue: 3(6), P. 100663 - 100663

Published: June 1, 2022

Language: Английский

Citations

322
Inflammatory profiles across the spectrum of disease reveal a distinct role for GM-CSF in severe COVID-19 DOI Creative Commons
Ryan S. Thwaites, Ashley Sanchez Sevilla Uruchurtu, Matthew K. Siggins

et al.

Science Immunology, Journal Year: 2021, Volume and Issue: 6(57)

Published: March 4, 2021

While it is now widely accepted that host inflammatory responses contribute to lung injury, the pathways drive severity and distinguish coronavirus disease 2019 (COVID-19) from other viral diseases remain poorly characterized. We analyzed plasma samples 471 hospitalized patients recruited through prospective multicenter ISARIC4C study 39 outpatients with mild disease, enabling extensive characterization of across a full spectrum COVID-19 severity. Progressive elevation levels numerous cytokines chemokines (including IL-6, CXCL10, GM-CSF) were associated accompanied by elevated markers endothelial injury thrombosis. Principal component network analyses demonstrated central roles for IL-6 GM-CSF in pathogenesis. Comparing these profiles archived fatal influenza, was equally both conditions whereas prominent only COVID-19. These findings further identify key inflammatory, thrombotic, vascular factors characterize severe

Language: Английский

Citations

215
Dexamethasone modulates immature neutrophils and interferon programming in severe COVID-19 DOI Creative Commons
Sarthak Sinha, Nicole L. Rosin, Rohit Arora

et al.

Nature Medicine, Journal Year: 2021, Volume and Issue: 28(1), P. 201 - 211

Published: Nov. 15, 2021

Abstract Although critical for host defense, innate immune cells are also pathologic drivers of acute respiratory distress syndrome (ARDS). Innate dynamics during Coronavirus Disease 2019 (COVID-19) ARDS, compared to ARDS from other pathogens, is unclear. Moreover, mechanisms underlying the beneficial effects dexamethasone severe COVID-19 remain elusive. Using single-cell RNA sequencing and plasma proteomics, we discovered that, bacterial was associated with expansion distinct neutrophil states characterized by interferon (IFN) prostaglandin signaling. Dexamethasone affected circulating neutrophils, altered IFN active downregulated interferon-stimulated genes activated IL-1R2 + neutrophils. expanded immunosuppressive immature neutrophils remodeled cellular interactions changing information receivers into providers. Male patients had higher proportions preferential steroid-induced expansion, potentially affecting outcomes. Our atlas (see ‘Data availability’ section) defines COVID-19-enriched molecular action develop targeted immunotherapies COVID-19.

Language: Английский

Citations

197
Adaptive Immune Responses and Immunity to SARS-CoV-2 DOI Creative Commons
Dragan Primorac,

Kristijan Vrdoljak,

Petar Brlek

et al.

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: May 4, 2022

Since the onset of COVID-19 pandemic, medical field has been forced to apply basic knowledge immunology with most up-to-date SARS-CoV-2 findings and translate it population whole world in record time. Following infection viral antigen, adaptive immune responses are activated mainly by particle encounters antigen-presenting cells or B cell receptors, which induce further biological interactions defend host against virus. After warded off, immunological memory is developed. The SARS-CoV cellular immunity shown persist even 17 years after infection, despite undetectable humoral component. Similar demonstrated for T a shorter period assessing interferon-gamma levels when heparinized blood stimulated virus-specific peptides. also play an irreplaceable part reaction as backbone response. They both provide signals activation maturation, competence, production IgA was be significant influence mediating mucosal first defense mechanism development nasal vaccines. Here, we interpret recent available research, encompasses significance current understanding activity, compare among naive, exposed, vaccinated donors. Our data showed that those who recovered from EMA-approved vaccines had long-lasting immunity. Additionally, analyze immunocompromised patients mediated impact clonality pandemic regarding breakthrough infections variants concern, B.1.617.2 (Delta) B.1.1.529 (Omicron) variants.

Language: Английский

Citations

98
Targeting immunometabolism against acute lung injury DOI Open Access

Li Ning,

Zou Shishi,

Bo Wang

et al.

Clinical Immunology, Journal Year: 2023, Volume and Issue: 249, P. 109289 - 109289

Published: March 12, 2023

Language: Английский

Citations

43
Distinct immunological signatures discriminate severe COVID-19 from non-SARS-CoV-2-driven critical pneumonia DOI Creative Commons
Stefanie Kreutmair, Susanne Unger, Nicolás Gonzalo Núñez

et al.

Immunity, Journal Year: 2021, Volume and Issue: 54(7), P. 1578 - 1593.e5

Published: May 9, 2021

Language: Английский

Citations

85
Role of IL-6 in the commitment of T cell subsets DOI Creative Commons
Thomas Korn, Michael Hiltensperger

Cytokine, Journal Year: 2021, Volume and Issue: 146, P. 155654 - 155654

Published: July 26, 2021

IL-6 gained much attention with the discovery that this cytokine is a non-redundant differentiation factor for Th17 cells and T follicular helper cells. Adaptive immune responses to fungi extracellular bacteria are impaired in absence of IL-6. also required induction ROR-γt+ Treg cells, which gatekeepers homeostasis gut lamina propria presence commensal bacteria. Conversely, severe immunopathology cell-mediated autoimmunity mediated by rely on their generation maintenance. Recently, it has been discovered these distinct cell subsets may be linked signaling modalities Here, we summarize current knowledge mode action maintenance propose context-dependent understanding impact might inform rational IL-6-directed interventions chronic inflammation.

Language: Английский

Citations

79
Liquid biomarkers of macrophage dysregulation and circulating spike protein illustrate the biological heterogeneity in patients with post‐acute sequelae of COVID‐19 DOI Creative Commons
Christoph Schultheiß, Edith Willscher, Lisa Paschold

et al.

Journal of Medical Virology, Journal Year: 2022, Volume and Issue: 95(1)

Published: Dec. 2, 2022

Post-acute sequelae of COVID-19 (PASC) are long-term consequences SARS-CoV-2 infection that can substantially impair the quality life. Underlying mechanisms ranging from persistent viruses to innate and adaptive immune dysregulation have been discussed. Here, we profiled plasma 181 individuals cohort study for digital health research in Germany (DigiHero), including after mild moderate with or without PASC uninfected controls. We focused on soluble factors related monocyte/macrophage biology circulating spike (S1) protein as a potential biomarker viral reservoirs. At median time 8 months infection, found pronounced almost all tested factors, both pro-inflammatory pro-fibrotic cytokines. These immunological perturbations were remarkably independent ongoing symptoms per se, but further correlation regression analyses suggested PASC-specific patterns involving CCL2/MCP-1 IL-8 either correlated sCD162, sCD206/MMR, IFN-α2, IL-17A IL-33, IL-18 IL-23. None analyzed detectability levels S1, indicating this represents an subset patients PASC. data confirm prior evidence persistence illustrate its biological heterogeneity still awaits clinically defined subtypes.

Language: Английский

Citations

65
COVID-19 Mechanisms in the Human Body—What We Know So Far DOI Creative Commons
Ashutosh Kumar, Ravi Kant Narayan, Pranav Prasoon

et al.

Frontiers in Immunology, Journal Year: 2021, Volume and Issue: 12

Published: Nov. 1, 2021

More than one and a half years have elapsed since the commencement of coronavirus disease 2019 (COVID-19) pandemic, world is struggling to contain it. Being caused by previously unknown virus, in initial period, there had been an extreme paucity knowledge about mechanisms, which hampered preventive therapeutic measures against COVID-19. In endeavor understand pathogenic extensive experimental studies conducted across globe involving cell culture-based experiments, human tissue organoids, animal models, targeted various aspects disease, viz., viral properties, tropism organ-specific pathogenesis, involvement physiological systems, immune response infection. The vastly accumulated scientific on all COVID-19 has currently changed scenario from great despair hope. Even though spectacular progress made these aspects, multiple gaps are remaining that need be addressed future studies. Moreover, severe acute respiratory syndrome 2 (SARS-CoV-2) variants emerged onset first wave, with seemingly greater transmissibility/virulence escape capabilities wild-type strain. this review, we narrate pandemic regarding mechanisms body, including virus-host interactions, pulmonary other systemic manifestations, immunological dysregulations, complications, host-specific vulnerability, long-term health consequences survivors. Additionally, provide brief review current evidence explaining molecular imparting transmissibility virulence emerging SARS-CoV-2 variants.

Language: Английский

Citations

64