SARS-CoV-2 triggered neutrophil extracellular traps (NETs) mediate COVID-19 pathology

Abstract

Severe COVID-19 patients develop acute respiratory distress syndrome that may progress to respiratory failure. These patients also develop cytokine storm syndrome, and organ dysfunctions, which is a clinical picture that resembles sepsis. Considering that neutrophil extracellular traps (NETs) have been described as an important factors of tissue damage in sepsis, we investigated whether NETs would be produced in COVID-19 patients and participate in the lung tissue damage. A cohort of 32 hospitalized patients with a confirmed diagnosis of COVID-19 and respective healthy controls were enrolled. NETs concentration was assessed by MPO-DNA PicoGreen assay or by confocal immunofluorescence. The cytotoxic effect of SARS-CoV-2-induced NETs was analyzed in human epithelial lung cells (A549 cells). The concentration of NETs was augmented in plasma and tracheal aspirate from COVID-19 patients and their neutrophils spontaneously released higher levels of NETs. NETs were also found in the lung tissue specimens from autopsies of COVID-19 patients. Notably, viable SARS-CoV-2 can directly induce in vitro release of NETs by healthy neutrophils in a PAD-4-dependent manner. 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 represent a potential therapeutic target for COVID-19.

African Americans and European Americans exhibit distinct gene expression patterns across tissues and tumors that are associated with immunologic and infectious functions and environmental exposures

“…CCL3 is a neutrophil chemotaxis protein, recruiting and activating granulocytes, and inhibiting HIV-1-infection 42 . CCL3L3 is upregulated in COVID-19, and neutrophils themselves are highly implicated in COVID-19 severity 41,43 . GSTM1, more highly expressed in African Americans compared to European Americans in almost every sample-type evaluated, is a key enzyme in mitochondrial ROS metabolism 44 .…”

Targeting Neutrophils to Treat Acute Respiratory Distress Syndrome in Coronavirus Disease

“…Peptidylarginine deiminase 4 (PAD4), NE, and gasdermin D along with free DNA, all participate in the NET formation ( Nathan, 2020 ). NETs are prevalent in blood, trachea, and lung specimens of COVID-19 patients ( Veras et al, 2020 ). Moreover, SARS-CoV-2 stimulates neutrophils from healthy donors into forming NETs, which can cause apoptosis in respiratory epithelial cells in vitro ( Oubihi and Wang, 2020 ).…”

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“…In COVID-19, evidence of extensive NETosis can be observed in infected lungs, 18 – 21 and SARS-CoV-2 virions have been shown to infect and induce NETosis of healthy neutrophils in vitro . 20 These reports implicate TLR-7 and/or TLR-8 in inducing NETosis of neutrophils at the site of infection. 20 , 43 Notably, TLR-7 and TLR-8 are ssRNA receptors with numerous substrates identified in the SARS-CoV-2 genome.…”

“…Both SARS-CoV-2 virions and serum/plasma from COVID-19 patients have been shown to induce NETosis of neutrophils isolated from healthy donors in vitro , consistent with both the local and peripheral inflammatory responses observed in COVID-19. 19 , 21 , 22 However, the specific signals that induce NETosis in viral disease remain an open question; viral ligands for toll-like receptors (TLRs), host damage-associated molecular patterns, antiviral cytokines (e.g., IL-8 and IFNγ), and activated platelets have all been implicated, but which if any of these is sufficient to induce NETosis is still debated. 21 , 23 Beyond viral disease, NETosis has been demonstrably linked to numerous inflammatory pathologies, including thrombosis and sepsis, both of which are observed in patients with COVID-19.…”