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1.
Blood ; 138(25): 2702-2713, 2021 12 23.
Article in English | MEDLINE | ID: covidwho-1365304

ABSTRACT

Multiple organ dysfunction is the most severe outcome of sepsis progression and is highly correlated with a worse prognosis. Excessive neutrophil extracellular traps (NETs) are critical players in the development of organ failure during sepsis. Therefore, interventions targeting NET release would likely effectively prevent NET-based organ injury associated with this disease. Herein, we demonstrate that the pore-forming protein gasdermin D (GSDMD) is active in neutrophils from septic humans and mice and plays a crucial role in NET release. Inhibition of GSDMD with disulfiram or genic deletion abrogated NET formation, reducing multiple organ dysfunction and sepsis lethality. Mechanistically, we demonstrate that during sepsis, activation of the caspase-11/GSDMD pathway controls NET release by neutrophils during sepsis. In summary, our findings uncover a novel therapeutic use for disulfiram and suggest that GSDMD is a therapeutic target to improve sepsis treatment.


Subject(s)
Extracellular Traps/genetics , Gene Deletion , Intracellular Signaling Peptides and Proteins/genetics , Multiple Organ Failure/genetics , Phosphate-Binding Proteins/genetics , Sepsis/genetics , Acetaldehyde Dehydrogenase Inhibitors/therapeutic use , Adoptive Transfer , Aged , Animals , Cells, Cultured , Disulfiram/therapeutic use , Female , Humans , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Male , Mice, Inbred C57BL , Middle Aged , Multiple Organ Failure/pathology , Multiple Organ Failure/therapy , Phosphate-Binding Proteins/antagonists & inhibitors , Sepsis/pathology , Sepsis/therapy
2.
PLoS Comput Biol ; 17(3): e1008810, 2021 03.
Article in English | MEDLINE | ID: covidwho-1121603

ABSTRACT

Abnormal coagulation and an increased risk of thrombosis are features of severe COVID-19, with parallels proposed with hemophagocytic lymphohistiocytosis (HLH), a life-threating condition associated with hyperinflammation. The presence of HLH was described in severely ill patients during the H1N1 influenza epidemic, presenting with pulmonary vascular thrombosis. We tested the hypothesis that genes causing primary HLH regulate pathways linking pulmonary thromboembolism to the presence of SARS-CoV-2 using novel network-informed computational algorithms. This approach led to the identification of Neutrophils Extracellular Traps (NETs) as plausible mediators of vascular thrombosis in severe COVID-19 in children and adults. Taken together, the network-informed analysis led us to propose the following model: the release of NETs in response to inflammatory signals acting in concert with SARS-CoV-2 damage the endothelium and direct platelet-activation promoting abnormal coagulation leading to serious complications of COVID-19. The underlying hypothesis is that genetic and/or environmental conditions that favor the release of NETs may predispose individuals to thrombotic complications of COVID-19 due to an increase risk of abnormal coagulation. This would be a common pathogenic mechanism in conditions including autoimmune/infectious diseases, hematologic and metabolic disorders.


Subject(s)
COVID-19/complications , COVID-19/genetics , Extracellular Traps/genetics , Lymphohistiocytosis, Hemophagocytic/complications , Lymphohistiocytosis, Hemophagocytic/genetics , Models, Biological , SARS-CoV-2/genetics , Thrombosis/etiology , Thrombosis/genetics , Algorithms , Cell Degranulation/genetics , Computational Biology , Gene Expression Regulation , Gene Regulatory Networks , Genetic Predisposition to Disease , Humans , Pandemics , Protein Interaction Maps , Pulmonary Embolism/etiology , Pulmonary Embolism/genetics , Viral Proteins/genetics
3.
Front Immunol ; 11: 2063, 2020.
Article in English | MEDLINE | ID: covidwho-868947

ABSTRACT

Background: Cases of excessive neutrophil counts in the blood in severe coronavirus disease (COVID-19) patients have drawn significant attention. Neutrophil infiltration was also noted on the pathological findings from autopsies. It is urgent to clarify the pathogenesis of neutrophils leading to severe pneumonia in COVID-19. Methods: A retrospective analysis was performed on 55 COVID-19 patients classified as mild (n = 22), moderate (n = 25), and severe (n = 8) according to the Guidelines released by the National Health Commission of China. Trends relating leukocyte counts and lungs examined by chest CT scan were quantified by Bayesian inference. Transcriptional signatures of host immune cells of four COVID19 patients were analyzed by RNA sequencing of lung specimens and BALF. Results: Neutrophilia occurred in 6 of 8 severe patients at 7-19 days after symptom onset, coinciding with lesion progression. Increasing neutrophil counts paralleled lesion CT values (slope: 0.8 and 0.3-1.2), reflecting neutrophilia-induced lung injury in severe patients. Transcriptome analysis revealed that neutrophil activation was correlated with 17 neutrophil extracellular trap (NET)-associated genes in COVID-19 patients, which was related to innate immunity and interacted with T/NK/B cells, as supported by a protein-protein interaction network analysis. Conclusion: Excessive neutrophils and associated NETs could explain the pathogenesis of lung injury in COVID-19 pneumonia.


Subject(s)
Betacoronavirus/genetics , Coronavirus Infections/immunology , Extracellular Traps/genetics , Neutrophil Activation/genetics , Neutrophils/immunology , Pneumonia, Viral/immunology , Adult , Aged , Bayes Theorem , COVID-19 , Coronavirus Infections/virology , Female , Humans , Leukocyte Count , Lung Injury/immunology , Lung Injury/pathology , Male , Middle Aged , Neutrophil Infiltration/immunology , Pandemics , Pneumonia, Viral/virology , Protein Interaction Maps/immunology , RNA, Viral/genetics , Retrospective Studies , SARS-CoV-2 , Transcriptome
4.
Platelets ; 32(3): 314-324, 2021 Apr 03.
Article in English | MEDLINE | ID: covidwho-748271

ABSTRACT

Platelets are increasingly being recognized for playing roles beyond thrombosis and hemostasis. Today we know that they mediate inflammation by direct interactions with innate immune cells or secretion of cytokines/chemokines. Here we review their interactions with neutrophils and monocytes/macrophages in infection and sepsis, stroke, myocardial infarction and venous thromboembolism. We discuss new roles for platelet surface receptors like GPVI or GPIb and also look at platelet contributions to the formation of neutrophil extracellular traps (NETs) as well as to deep vein thrombosis during infection, e.g. in COVID-19 patients.


Subject(s)
Blood Platelets/immunology , COVID-19/immunology , Myocardial Infarction/immunology , Neutrophils/immunology , Sepsis/immunology , Stroke/immunology , Venous Thromboembolism/immunology , Blood Platelets/pathology , COVID-19/genetics , COVID-19/pathology , COVID-19/virology , Cell Communication/genetics , Cell Communication/immunology , Cytokines/genetics , Cytokines/immunology , Extracellular Traps/genetics , Extracellular Traps/immunology , Gene Expression Regulation , Humans , Inflammation , Macrophages/immunology , Macrophages/pathology , Monocytes/immunology , Monocytes/pathology , Myocardial Infarction/genetics , Myocardial Infarction/pathology , Neutrophils/pathology , Platelet Glycoprotein GPIb-IX Complex/genetics , Platelet Glycoprotein GPIb-IX Complex/immunology , Platelet Membrane Glycoproteins/genetics , Platelet Membrane Glycoproteins/immunology , Sepsis/genetics , Sepsis/pathology , Stroke/genetics , Stroke/pathology , Venous Thromboembolism/genetics , Venous Thromboembolism/pathology
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