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Neutrophil Extracellular Traps, Sepsis and COVID-19 - A Tripod Stand.

ABSTRACT: The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the current coronavirus disease 2019 (COVID-19) pandemic. Majority of COVID-19 patients have mild disease but about 20% of COVID-19 patients progress to severe disease. These patients end up in the intensive care unit (ICU) with clinical manifestations of acute respiratory distress syndrome (ARDS) and sepsis. The formation of neutrophil extracellular traps (NETs) has also been associated with severe COVID-19. Understanding of the immunopathology of COVID-19 is critical for the development of effective therapeutics. In this article, we discuss evidence indicating that severe COVID-19 has clinical presentations consistent with the definitions of viral sepsis. We highlight the role of neutrophils and NETs formation in the pathogenesis of severe COVID-19. Finally, we highlight the potential of therapies inhibiting NETs formation for the treatment of COVID-19.

SUBMITTER: Ventura-Santana E

PROVIDER: S-EPMC9226304 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Neutrophil Extracellular Traps, Sepsis and COVID-19 - A Tripod Stand.

Ventura-Santana Esmeiry E Ninan Joshua R JR Snyder Caitlin M CM Okeke Emeka B EB

Frontiers in immunology 20220610

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the current coronavirus disease 2019 (COVID-19) pandemic. Majority of COVID-19 patients have mild disease but about 20% of COVID-19 patients progress to severe disease. These patients end up in the intensive care unit (ICU) with clinical manifestations of acute respiratory distress syndrome (ARDS) and sepsis. The formation of neutrophil extracellular traps (NETs) has also been associated with severe COVID-1 ...[more]

PMID: 35757734

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Neutrophil extracellular traps in COVID-19.

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| S-EPMC7308057 | biostudies-literature

Autoantibodies stabilize neutrophil extracellular traps in COVID-19.

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| S-EPMC8410057 | biostudies-literature

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Excessive Neutrophils and Neutrophil Extracellular Traps in COVID-19.

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| S-EPMC7161085 | biostudies-literature

Vascular occlusion by neutrophil extracellular traps in COVID-19.

Project description:BackgroundCoronavirus induced disease 2019 (COVID-19) can be complicated by severe organ damage leading to dysfunction of the lungs and other organs. The processes that trigger organ damage in COVID-19 are incompletely understood.MethodsSamples were donated from hospitalized patients. Sera, plasma, and autopsy-derived tissue sections were examined employing flow cytometry, enzyme-linked immunosorbent assays, and immunohistochemistry.Patient findingsHere, we show that severe COVID-19 is characterized by a highly pronounced formation of neutrophil extracellular traps (NETs) inside the micro-vessels. Intravascular aggregation of NETs leads to rapid occlusion of the affected vessels, disturbed microcirculation, and organ damage. In severe COVID-19, neutrophil granulocytes are strongly activated and adopt a so-called low-density phenotype, prone to spontaneously form NETs. In accordance, markers indicating NET turnover are consistently increased in COVID-19 and linked to disease severity. Histopathology of the lungs and other organs from COVID-19 patients showed congestions of numerous micro-vessels by aggregated NETs associated with endothelial damage.InterpretationThese data suggest that organ dysfunction in severe COVID-19 is associated with excessive NET formation and vascular damage.FundingDeutsche Forschungsgemeinschaft (DFG), EU, Volkswagen-Stiftung.

| S-EPMC7397705 | biostudies-literature

On the Origin of Neutrophil Extracellular Traps in COVID-19.

Project description:Despite ongoing vaccination COVID-19 is a global healthcare problem because of the lack of an effective targeted therapy. In severe COVID-19 manifesting as acute respiratory distress syndrome, uncontrolled innate immune system activation results in cytokine deregulation, damage-associated molecular patterns release upon tissue damage and high occurrence of thrombotic events. These pathomechanisms are linked to neutrophil function and dysfunction, particularly increased formation of neutrophil extracellular traps (NETs). While the association of NETs and severity of COVID-19 has been shown and proved, the causes of NETs formation are unclear. The aim of this review is to summarize potential inducers of NETs formation in severe COVID-19 and to discuss potential treatment options targeting NETs formation of removal.

| S-EPMC8961727 | biostudies-literature

Neutrophil Extracellular Traps in Fatal COVID-19-Associated Lung Injury.

Project description:An excess formation of neutrophil extracellular traps (NETs), previously shown to be strongly associated with cytokine storm and acute respiratory distress syndrome (ARDS) with prevalent endothelial dysfunction and thrombosis, has been postulated to be a central factor influencing the pathophysiology and clinical presentation of severe COVID-19. A growing number of serological and morphological evidence has added to this assumption, also in regard to potential treatment options. In this study, we used immunohistochemistry and histochemistry to trace NETs and their molecular markers in autopsy lung tissue from seven COVID-19 patients. Quantification of key immunomorphological features enabled comparison with non-COVID-19 diffuse alveolar damage. Our results strengthen and extend recent findings, confirming that NETs are abundantly present in seriously damaged COVID-19 lung tissue, especially in association with microthrombi of the alveolar capillaries. In addition, we provide evidence that low-density neutrophils (LDNs), which are especially prone to NETosis, contribute substantially to COVID-19-associated lung damage in general and vascular blockages in particular.

| S-EPMC8337148 | biostudies-literature

Neutrophil extracellular traps (NETs) exacerbate severity of infant sepsis.

Project description:BackgroundNeutrophil extracellular traps (NETs) are innate defense mechanisms that are also implicated in the pathogenesis of organ dysfunction. However, the role of NETs in pediatric sepsis is unknown.MethodsInfant (2 weeks old) and adult (6 weeks old) mice were submitted to sepsis by intraperitoneal (i.p.) injection of bacteria suspension or lipopolysaccharide (LPS). Neutrophil infiltration, bacteremia, organ injury, and concentrations of cytokine, NETs, and DNase in the plasma were measured. Production of reactive oxygen and nitrogen species and release of NETs by neutrophils were also evaluated. To investigate the functional role of NETs, mice undergoing sepsis were treated with antibiotic plus rhDNase and the survival, organ injury, and levels of inflammatory markers and NETs were determined. Blood samples from pediatric and adult sepsis patients were collected and the concentrations of NETs measured.ResultsInfant C57BL/6 mice subjected to sepsis or LPS-induced endotoxemia produced significantly higher levels of NETs than the adult mice. Moreover, compared to that of the adult mice, this outcome was accompanied by increased organ injury and production of inflammatory cytokines. The increased NETs were associated with elevated expression of Padi4 and histone H3 citrullination in the neutrophils. Furthermore, treatment of infant septic mice with rhDNase or a PAD-4 inhibitor markedly attenuated sepsis. Importantly, pediatric septic patients had high levels of NETs, and the severity of pediatric sepsis was positively correlated with the level of NETs.ConclusionThis study reveals a hitherto unrecognized mechanism of pediatric sepsis susceptibility and suggests that NETs represents a potential target to improve clinical outcomes of sepsis.

| S-EPMC6454713 | biostudies-literature

SARS-CoV-2-triggered neutrophil extracellular traps mediate COVID-19 pathology.

Project description:Severe COVID-19 patients develop acute respiratory distress syndrome that may progress to cytokine storm syndrome, organ dysfunction, and death. Considering that neutrophil extracellular traps (NETs) have been described as important mediators of tissue damage in inflammatory diseases, we investigated whether NETs would be involved in COVID-19 pathophysiology. A cohort of 32 hospitalized patients with a confirmed diagnosis of COVID-19 and healthy controls were enrolled. The concentration of NETs was augmented in plasma, tracheal aspirate, and lung autopsies tissues from COVID-19 patients, and their neutrophils released higher levels of NETs. Notably, we found that viable SARS-CoV-2 can directly induce the release of NETs by healthy neutrophils. Mechanistically, NETs triggered by SARS-CoV-2 depend on angiotensin-converting enzyme 2, serine protease, virus replication, and PAD-4. Finally, NETs released by SARS-CoV-2-activated neutrophils promote lung epithelial cell death in vitro. These results unravel a possible detrimental role of NETs in the pathophysiology of COVID-19. Therefore, the inhibition of NETs represents a potential therapeutic target for COVID-19.

| S-EPMC7488868 | biostudies-literature

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