Dynamic dysregulation of IL-6 and genes functional in NETosis, complement and coagulation in severe COVID-19 illness

Mukhopadhyay, Samanwoy; Sinha, Subrata; Mohapatra, Saroj Kant

doi:10.1101/2020.10.13.20211425

Cited by 3 publications

(2 citation statements)

References 32 publications

(82 reference statements)

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“…To look for a transcriptomic signature of virally-induced NETosis and its associations with disease outcomes, we defined a NETosis metagene score composed of PADI4, MPO, ELANE, TNF, CXCL8, GSDMD, and TLR3 genes (Figure S14A-E), encoding protein components of NETs, signaling inducers and the viral double-stranded (ds)DNA-sensing receptor TLR3 (Figure S14A). Our score correlated strongly with a previously-defined NETosis gene signature (Figure S14B) 51 . The analysis revealed a significant enrichment of the NETosis metagene score on Days 3 and 7 in severe patients compared to non-severe patients (Figure 4A).…”

Section: Longitudinal Analyses Reveal Diverging Pathway Dynamics Between Survivors and Non-survivors Among Severe Patientssupporting

confidence: 77%

Longitudinal characterization of circulating neutrophils uncovers distinct phenotypes associated with disease severity in hospitalized COVID-19 patients

LaSalle

Gonye

Freeman

et al. 2021

Preprint

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Multiple studies have identified an association between neutrophils and COVID-19 disease severity; however, the mechanistic basis of this association remains incompletely understood. Here we collected 781 longitudinal blood samples from 306 hospitalized COVID-19+ patients, 78 COVID-19- acute respiratory distress syndrome patients, and 8 healthy controls, and performed bulk RNA-sequencing of enriched neutrophils, plasma proteomics, cfDNA measurements and high throughput antibody profiling assays to investigate the relationship between neutrophil states and disease severity or death. We identified dynamic switches between six distinct neutrophil subtypes using non-negative matrix factorization (NMF) clustering. At days 3 and 7 post-hospitalization, patients with severe disease had an enrichment of a granulocytic myeloid derived suppressor cell-like state gene expression signature, while non-severe patients with resolved disease were enriched for a progenitor-like immature neutrophil state signature. Severe disease was associated with gene sets related to neutrophil degranulation, neutrophil extracellular trap (NET) signatures, distinct metabolic signatures, and enhanced neutrophil activation and generation of reactive oxygen species (ROS). We found that the majority of patients had a transient interferon-stimulated gene signature upon presentation to the emergency department (ED) defined here as Day 0, regardless of disease severity, which persisted only in patients who subsequently died. Humoral responses were identified as potential drivers of neutrophil effector functions, as enhanced antibody-dependent neutrophil phagocytosis and reduced NETosis was associated with elevated SARS-CoV-2-specific IgG1-to-IgA1 ratios in plasma of severe patients who survived. In vitro experiments confirmed that while patient-derived IgG antibodies mostly drove neutrophil phagocytosis and ROS production in healthy donor neutrophils, patient-derived IgA antibodies induced a predominant NETosis response. Overall, our study demonstrates neutrophil dysregulation in severe COVID-19 and a potential role for IgA-dominant responses in driving neutrophil effector functions in severe disease and mortality.

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Section: Longitudinal Analyses Reveal Diverging Pathway Dynamics Between Survivors and Non-survivors Among Severe Patientssupporting

confidence: 77%

Longitudinal characterization of circulating neutrophils uncovers distinct phenotypes associated with disease severity in hospitalized COVID-19 patients

LaSalle

Gonye

Freeman

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Haem and ATP) and elevated cytokine levels are all implicated, especially IL-8: a potent neutrophil chemoattractant [ 39 ]. A recent study suggests that IL-6-driven complement elevation plays a role in NET formation, as activated neutrophils are known to have surfaces liable to complement binding, but also will respond to anaphylatoxins (C3a and C5a) via complement receptors [ 120 ].…”

Section: Introductionmentioning

confidence: 99%

Innate immunology in COVID-19—a living review. Part II: dysregulated inflammation drives immunopathology

Prs.

Alrubayyi

Pring

et al. 2020

Oxford Open Immunology

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The current pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a global health crisis and will likely continue to impact public health for years. As the effectiveness of the innate immune response is crucial to patient outcome, huge efforts have been made to understand how dysregulated immune responses may contribute to disease progression. Here we have reviewed current knowledge of cellular innate immune responses to SARS-CoV-2 infection, highlighting areas for further investigation and suggesting potential strategies for intervention. We conclude that in severe COVID-19 initial innate responses, primarily type I interferon, are suppressed or sabotaged which results in an early interleukin (IL)-6, IL-10 and IL-1β-enhanced hyperinflammation. This inflammatory environment is driven by aberrant function of innate immune cells: monocytes, macrophages and natural killer cells dispersing viral pathogen-associated molecular patterns and damage-associated molecular patterns into tissues. This results in primarily neutrophil-driven pathology including fibrosis that causes acute respiratory distress syndrome. Activated leukocytes and neutrophil extracellular traps also promote immunothrombotic clots that embed into the lungs and kidneys of severe COVID-19 patients, are worsened by immobility in the intensive care unit and are perhaps responsible for the high mortality. Therefore, treatments that target inflammation and coagulation are promising strategies for reducing mortality in COVID-19.

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A lower admission level of interleukin-6 is associated with first-pass effect in ischemic stroke patients

Mechtouff

Bochaton

Paccalet

et al. 2021

J NeuroIntervent Surg

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BackgroundFirst-pass effect (FPE) defined as a complete or near-complete reperfusion achieved after a single thrombectomy pass is predictive of favorable outcome in acute ischemic stroke (AIS) patients. We aimed to assess whether admission levels of inflammatory markers are associated with FPE.MethodsHIBISCUS-STROKE (CoHort of Patients to Identify Biological and Imaging markerS of CardiovascUlar Outcomes in Stroke) includes AIS patients with large vessel occlusion treated with mechanical thrombectomy following brain MRI. C-reactive protein, interleukin (IL)-6, IL-8, IL-10, monocyte chemoattractant protein-1, soluble tumor necrosis factor receptor I, soluble form suppression of tumorigenicity 2, matrix metalloproteinase-9 (MMP-9), soluble P-selectin, and vascular cellular adhesion molecule-1 were measured in admission sera using an ELISA assay. FPE was defined as a complete or near-complete reperfusion (thrombolysis in cerebral infarction scale (TICI) 2c or 3) after the first pass. A multivariate logistic regression analysis was performed to assess independent factors associated with FPE.ResultsA total of 151 patients were included. Among them, 43 (28.5%) patients had FPE. FPE was associated with low admission levels of IL-6, MMP-9, and platelet count, an older age, lack of hypertension, lack of tandem occlusion, a shorter thrombus length, and a reduced procedural time. Following multivariate analysis, a low admission level of IL-6 was associated with FPE (OR 0.66, 95% CI 0.46 to 0.94). Optimal cut-off of IL-6 level for distinguishing FPE from non-FPE was 3.0 pg/mL (sensitivity 92.3%, specificity 42.3%).ConclusionA lower admission level of IL-6 is associated with FPE.

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Dynamic dysregulation of IL-6 and genes functional in NETosis, complement and coagulation in severe COVID-19 illness

Cited by 3 publications

References 32 publications

Longitudinal characterization of circulating neutrophils uncovers distinct phenotypes associated with disease severity in hospitalized COVID-19 patients

Longitudinal characterization of circulating neutrophils uncovers distinct phenotypes associated with disease severity in hospitalized COVID-19 patients

Innate immunology in COVID-19—a living review. Part II: dysregulated inflammation drives immunopathology

A lower admission level of interleukin-6 is associated with first-pass effect in ischemic stroke patients

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