Neutrophils in COVID-19: Not Innocent Bystanders

McKenna, Ellen; Wubben, Richard; Isaza-Correa, Johana M.; Melo, Ashanty M; Mhaonaigh, Aisling Ui; Conlon, Niall; O’Donnell, James S.; Cheallaigh, Clíona Ní; Hurley, Tim; Stevenson, Nigel J.; Little, Mark A.; Molloy, Eleanor J.

doi:10.3389/fimmu.2022.864387

Cited by 61 publications

(58 citation statements)

References 124 publications

(152 reference statements)

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“…The pathogenesis of these pulmonary complications in COVID-19 patients is not well-known. SARS-CoV-2 infect target cells by binding its S-protein to cellular ACE2, and human microvascular endothelial cells [ 18 , 19 , 20 ] and neutrophils [ 16 , 17 ] express ACE2. In the present study, we demonstrate that exposure of primary HLMEC to SARS-CoV-2 S-proteins induces transcriptional upregulation of TF and significantly increases the expression and secretion of Factor-V, thrombin, and fibrinogen, all of which are clotting factors known to activate the coagulation cascade and induce thromboinflammation [ 28 , 29 , 30 ].…”

Section: Discussionmentioning

confidence: 99%

“…RBD–PD interaction is critical for viral binding to cellular ACE2, entry, and infection of target cells [ 14 , 15 ]. There is evidence that neutrophils [ 16 , 17 ] and endothelial cells from different vascular beds [ 18 , 19 , 20 ] express ACE2. There is also evidence that viral S-proteins can be shed; are present in bodily fluids, microvessels, and tissues of SARS-CoV-2 infected patients; and can directly affect the vascular endothelium [ 12 , 21 , 22 , 23 , 24 ].…”

Section: Introductionmentioning

confidence: 99%

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SARS-CoV-2 Spike Proteins and Cell–Cell Communication Inhibits TFPI and Induces Thrombogenic Factors in Human Lung Microvascular Endothelial Cells and Neutrophils: Implications for COVID-19 Coagulopathy Pathogenesis

Bhargavan

Kanmogne

2022

IJMS

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In SARS-CoV-2-infected humans, disease progression is often associated with acute respiratory distress syndrome involving severe lung injury, coagulopathy, and thrombosis of the alveolar capillaries. The pathogenesis of these pulmonary complications in COVID-19 patients has not been elucidated. Autopsy study of these patients showed SARS-CoV-2 virions in pulmonary vessels and sequestrated leukocytes infiltrates associated with endotheliopathy and microvascular thrombosis. Since SARS-CoV-2 enters and infects target cells by binding its spike (S) protein to cellular angiotensin-converting enzyme 2 (ACE2), and there is evidence that vascular endothelial cells and neutrophils express ACE2, we investigated the effect of S-proteins and cell–cell communication on primary human lung microvascular endothelial cells (HLMEC) and neutrophils expression of thrombogenic factors and the potential mechanisms. Using S-proteins of two different SARS-CoV-2 variants (Wuhan and Delta), we demonstrate that exposure of HLMEC or neutrophils to S-proteins, co-culture of HLMEC exposed to S-proteins with non-exposed neutrophils, or co-culture of neutrophils exposed to S-proteins with non-exposed HLMEC induced transcriptional upregulation of tissue factor (TF), significantly increased the expression and secretion of factor (F)-V, thrombin, and fibrinogen and inhibited tissue factor pathway inhibitor (TFPI), the primary regulator of the extrinsic pathway of blood coagulation, in both cell types. Recombinant (r)TFPI and a thiol blocker (5,5′-dithio-bis-(2-nitrobenzoic acid)) prevented S-protein-induced expression and secretion of Factor-V, thrombin, and fibrinogen. Thrombomodulin blocked S-protein-induced expression and secretion of fibrinogen but had no effect on S-protein-induced expression of Factor-V or thrombin. These results suggests that following SARS-CoV-2 contact with the pulmonary endothelium or neutrophils and endothelial–neutrophil interactions, viral S-proteins induce coagulopathy via the TF pathway and mechanisms involving functional thiol groups. These findings suggest that using rTFPI and/or thiol-based drugs could be a viable therapeutic strategy against SARS-CoV-2-induced coagulopathy and thrombosis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 Spike Proteins and Cell–Cell Communication Inhibits TFPI and Induces Thrombogenic Factors in Human Lung Microvascular Endothelial Cells and Neutrophils: Implications for COVID-19 Coagulopathy Pathogenesis

Bhargavan

Kanmogne

2022

IJMS

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“…From a pathophysiological standpoint, the dysfunction of both the innate and adaptive immune responses characterize patients with severe COVID-19 [ 74 , 75 ]. Although increased neutrophils and neutrophil-to-lymphocyte ratio have been described in cases of severe COVID-19 [ 38 , 76 ], the active role of neutrophils in COVID-19 pathophysiology has been debated [ 77 ]. However, some pieces of evidence support their importance; SARS-CoV-2 can directly induce the release of neutrophil extracellular traps (NETs) from donor-derived neutrophils [ 78 ].…”

Section: Discussionmentioning

confidence: 99%

“…However, some pieces of evidence support their importance; SARS-CoV-2 can directly induce the release of neutrophil extracellular traps (NETs) from donor-derived neutrophils [ 78 ]. These web-like chromatin structures have a role in viral clearance, but excessive NET levels exacerbate inflammation in acute respiratory distress syndrome and have been associated with COVID-19 complications, ranging from thrombosis to CNS involvement [ 77 ]. Granulocytes and monocytes activated by a continuous and weak signal (e.g., cytokines) have an immature phenotype and produce immunosuppressive and anti-inflammatory factors [ 79 ].…”

Section: Discussionmentioning

confidence: 99%

Combining Deep Phenotyping of Serum Proteomics and Clinical Data via Machine Learning for COVID-19 Biomarker Discovery

Beltrami

Martino

Dalla

et al. 2022

IJMS

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the persistence of long-term coronavirus-induced disease 2019 (COVID-19) sequelae demands better insights into its natural history. Therefore, it is crucial to discover the biomarkers of disease outcome to improve clinical practice. In this study, 160 COVID-19 patients were enrolled, of whom 80 had a “non-severe” and 80 had a “severe” outcome. Sera were analyzed by proximity extension assay (PEA) to assess 274 unique proteins associated with inflammation, cardiometabolic, and neurologic diseases. The main clinical and hematochemical data associated with disease outcome were grouped with serological data to form a dataset for the supervised machine learning techniques. We identified nine proteins (i.e., CD200R1, MCP1, MCP3, IL6, LTBP2, MATN3, TRANCE, α2-MRAP, and KIT) that contributed to the correct classification of COVID-19 disease severity when combined with relative neutrophil and lymphocyte counts. By analyzing PEA, clinical and hematochemical data with statistical methods that were able to handle many variables in the presence of a relatively small sample size, we identified nine potential serum biomarkers of a “severe” outcome. Most of these were confirmed by literature data. Importantly, we found three biomarkers associated with central nervous system pathologies and protective factors, which were downregulated in the most severe cases.

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“…Ilya I. Mechnikov discovered that phagocytes and phagocytosis are the basis of natural cellular immunity, and macrophages and microphages, later renamed neutrophils, are the first line of defense in the host’s response to damage, infection, and tissue repair [ 1 ]. Neutrophils are fast and strong, and protect the body in all pathologies [ 2 , 3 , 4 , 5 , 6 ]. In this context, the study of the functions of neutrophils in health and disease is of great interest and importance.…”

mentioning

confidence: 99%