High Levels of Neutrophil Extracellular Traps Persist in the Lower Respiratory Tract of Critically Ill Patients With Coronavirus Disease 2019

Ouwendijk, Werner J. D.; Raadsen, Matthijs P.; Kampen, Jeroen J.A. van; Verdijk, Robert M.; Thüsen, Jan H. von der; Guo, Lihui; Hoek, Rogier A.S.; Akker, Johannes P. C. van den; Endeman, Henrik; Langerak, Thomas; Molenkamp, Richard; Gommers, Diederik; Koopmans, Marion; Gorp, Eric C. M. Van; Verjans, Georges M. G. M.; Haagmans, Bart L.

doi:10.1093/infdis/jiab050

Cited by 56 publications

(65 citation statements)

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“…In this context, one study which included 75 critical patients and seven healthy subjects demonstrated that, during the course of COVID-19, the levels of NETs remained high in samples from the lower respiratory tract. In keeping with this, NETs were detected in lung tissue from deceased COVID-19 patients, specifically in the bronchi and alveolar spaces [ 73 ]. The same study showed that the levels of NETs biomarkers, specifically of MPO-DNA complexes, correlated both with viral load in sputum samples (Spearman r correlation: r = 0.16, p = 0.009) and with neutrophil-recruiting chemokines (CXCL10) in blood (Spearman r correlation: r = 0.259, p = 0.026) [ 73 ].…”

Section: Neutrophils and Neutrophil Extracellular Traps In Covid-19mentioning

confidence: 88%

“…The same study showed that the levels of NETs biomarkers, specifically of MPO-DNA complexes, correlated both with viral load in sputum samples (Spearman r correlation: r = 0.16, p = 0.009) and with neutrophil-recruiting chemokines (CXCL10) in blood (Spearman r correlation: r = 0.259, p = 0.026) [ 73 ]. Thus, it would seem that NETs are released and retained in the lower respiratory tract of critical COVID-19 patients, hence contributing to SARS-CoV-2-induced ARDS condition [ 73 ].…”

Section: Neutrophils and Neutrophil Extracellular Traps In Covid-19mentioning

confidence: 99%

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Role of Neutrophil Extracellular Traps in COVID-19 Progression: An Insight for Effective Treatment

et al. 2021

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The coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, has resulted in a pandemic with over 270 million confirmed cases and 5.3 million deaths worldwide. In some cases, the infection leads to acute respiratory distress syndrome (ARDS), which is triggered by a cytokine storm and multiple organ failure. Clinical hematological, biochemical, coagulation, and inflammatory markers, such as interleukins, are associated with COVID-19 disease progression. In this regard, neutrophilia, neutrophil-to-lymphocyte ratio (NLR), and neutrophil-to-albumin ratio (NAR), have emerged as promising biomarkers of disease severity and progression. In the pathophysiology of ARDS, the inflammatory environment induces neutrophil influx and activation in the lungs, promoting the release of cytokines, proteases, reactive oxygen species (ROS), and, eventually, neutrophil extracellular traps (NETs). NETs components, such as DNA, histones, myeloperoxidase, and elastase, may exert cytotoxic activity and alveolar damage. Thus, NETs have also been described as potential biomarkers of COVID-19 prognosis. Several studies have demonstrated that NETs are induced in COVID-19 patients, and that the highest levels of NETs are found in critical ones, therefore highlighting a correlation between NETs and severity of the disease. Knowledge of NETs signaling pathways, and the targeting of points of NETs release, could help to develop an effective treatment for COVID-19, and specifically for severe cases, which would help to manage the pandemic.

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Section: Neutrophils and Neutrophil Extracellular Traps In Covid-19mentioning

confidence: 88%

Section: Neutrophils and Neutrophil Extracellular Traps In Covid-19mentioning

confidence: 99%

Role of Neutrophil Extracellular Traps in COVID-19 Progression: An Insight for Effective Treatment

et al. 2021

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“…IL-8 is a potent pro-inflammatory cytokine that mediates the recruitment and activation of neutrophils during inflammation, and IL-8 may contribute to COVID-19 pathology. Indeed, excessive neutrophils and neutrophil extracellular traps are present in the lungs of critically ill COVID-19 patients [51], and they act as critical drivers of progressive pulmonary impairment [52]. Interestingly, we previously showed the upregulated expression of IL-8 receptor A (IL8RA) in Vero E6 cells infected with SARS-CoV [45], as well as sharp up-regulation of IL-8 receptor transcript β in HL-CZ cells expressing spike protein of SARS-CoV [15].…”

Section: Discussionmentioning

confidence: 99%

Comparative Transcriptomic and Molecular Pathway Analyses of HL-CZ Human Pro-Monocytic Cells Expressing SARS-CoV-2 Spike S1, S2, NP, NSP15 and NSP16 Genes

et al. 2021

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The ongoing COVID-19 pandemic is a clear and present threat to global public health. Research into how the causative SARS-CoV-2 virus together with its individual constituent genes and proteins interact with target host cells can facilitate the development of improved strategies to manage the acute and long-term complications of COVID-19. In this study, to better understand the biological roles of critical SARS-CoV-2 proteins, we determined and compared the host transcriptomic responses of the HL-CZ human pro-monocytic cell line upon transfection with key viral genes encoding the spike S1 subunit, S2 subunit, nucleocapsid protein (NP), NSP15 (endoribonuclease), and NSP16 (2′-O-ribose-methyltransferase). RNA sequencing followed by gene set enrichment analysis and other bioinformatics tools revealed that host genes associated with topologically incorrect protein, virus receptor activity, heat shock protein binding, endoplasmic reticulum stress, antigen processing and presentation were up-regulated in the presence of viral spike S1 expression. With spike S2 expression, pro-monocytic genes associated with the interferon-gamma-mediated signaling pathway, regulation of phosphatidylinositol 3-kinase activity, adipocytokine signaling pathway, and insulin signaling pathway were down-regulated, whereas those associated with cytokine-mediated signaling were up-regulated. The expression of NSP15 induced the up-regulation of genes associated with neutrophil degranulation, neutrophil-mediated immunity, oxidative phosphorylation, prion disease, and pathways of neurodegeneration. The expression of NSP16 resulted in the down-regulation of genes associated with S-adenosylmethionine-dependent methyltransferase activity. The expression of NP down-regulated genes associated with positive regulation of neurogenesis, nervous system development, and heart development. Taken together, the complex transcriptomic alterations arising from these viral-host gene interactions offer useful insights into host genes and their pathways that potentially contribute to SARS-CoV-2 pathogenesis.

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“…This chemical modification is critical in NETs release in SARS-CoV-2 [ 29 ], respiratory syncytial virus (RSV) [ 29 ], endotoxins from bacteria [ 30 ], and cryptococcus neoformans fungi [ 31 ]. NETs have been implicated in COVID-19 pathogenesis [ 20 ] and the ability for a PAD inhibitor to block the formation of citrullinated histones may offer therapeutic benefit to both the thrombotic and inflammatory effects observed in the viral infection.…”

Section: Overview Of Pads and Significance In Sars-cov-2mentioning

confidence: 99%

“…Mechanistically, the platelets forming the core of the clot constituents are shown to have marked adhesion to neutrophils when isolated from patients with severe COVID-19 infections [19]. Upon isolation of activated platelet-rich plasma from patients with severe COVID-19 infections, associated high NETs levels corresponded to the platelet-neutrophil adhesion, demonstrating that NETs could be acting as a key mediator for the formation of immunothrombosis in patients infected with the virus [20]. Neutrophil chromatin is non-pathologically found in a condensed state mediated through arginine (R) residues.…”

Section: Netosis and Citrullinated Histones Potentiate Immunothrombosismentioning

confidence: 99%

PAD Inhibitors as a Potential Treatment for SARS-CoV-2 Immunothrombosis

et al. 2021

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Since the discovery of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in December 2019, the virus’s dynamicity has resulted in the evolution of various variants, including the delta variant and the more novel mu variant. With a multitude of mutant strains posing as challenges to vaccine efficacy, it is critical that researchers embrace the development of pharmacotherapeutics specific to SARS-CoV-2 pathophysiology. Neutrophil extracellular traps and their constituents, including citrullinated histones, display a linear connection with thrombotic manifestations in COVID-19 patients. Peptidylarginine deiminases (PADs) are a group of enzymes involved in the modification of histone arginine residues by citrullination, allowing for the formation of NETs. PAD inhibitors, specifically PAD-4 inhibitors, offer extensive pharmacotherapeutic potential across a broad range of inflammatory diseases such as COVID-19, through mediating NETs formation. Although numerous PAD-4 inhibitors exist, current literature has not explored the depth of utilizing these inhibitors clinically to treat thrombotic complications in COVID-19 patients. This review article offers the clinical significance of PAD-4 inhibitors in reducing thrombotic complications across various inflammatory disorders like COVID-19 and suggests that these inhibitors may be valuable in treating the origin of SARS-CoV-2 immunothrombosis.

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High Levels of Neutrophil Extracellular Traps Persist in the Lower Respiratory Tract of Critically Ill Patients With Coronavirus Disease 2019

Cited by 56 publications

References 44 publications

Role of Neutrophil Extracellular Traps in COVID-19 Progression: An Insight for Effective Treatment

Role of Neutrophil Extracellular Traps in COVID-19 Progression: An Insight for Effective Treatment

Comparative Transcriptomic and Molecular Pathway Analyses of HL-CZ Human Pro-Monocytic Cells Expressing SARS-CoV-2 Spike S1, S2, NP, NSP15 and NSP16 Genes

PAD Inhibitors as a Potential Treatment for SARS-CoV-2 Immunothrombosis

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