COVID-19 patients who suffer life-threatening complications such as blood clots and inflammation also experience dysregulated NETosis. NETosis is a cell death process that generates neutrophil extracellular traps (NETs), extracellular webs of DNA and toxins that capture and kill pathogens. However, NETs may interact with platelets and form microthrombi that contribute to acute respiratory distress syndrome.

The correlation between excess NETs and the severity of COVID-19 has been clarified by researchers at the University of Utah (U of U) Health, PEEL Therapeutics, Cold Spring Harbor Laboratory (CSHL), and Weill Cornell Medicine. These researchers also report that the NETs induced by COVID-19 may be blocked by neonatal NET-Inhibitory Factor (nNIF).

Detailed findings appeared June 29 in the journal Blood, in an article titled, “Neutrophil Extracellular Traps (NETs) Contribute to Immunothrombosis in COVID-19 Acute Respiratory Distress Syndrome.” The article reported that blood samples were collected from 33 hospitalized patients, as well as autopsy tissue. The article also described how the blood and tissue samples were examined for biomarkers of NET formation, biomarkers such as plasma myeloperoxidase (MPO)-DNA complexes, platelet factor 4, RANTES, and selected cytokines.

“In this prospective cohort study, we demonstrate a robust correlation between NETs and severity of respiratory illness in COVID-19,” the article’s authors wrote. “We measure the highest levels of circulating NETs in COVID-19 patients with endotracheal intubation and report for the first time the infiltration of platelet co-localization with citrullinated histone H3 positive neutrophils likely undergoing NETosis in the pulmonary microthrombi of patients who died from COVID-19.”

The researchers found that biomarkers of NET formation were more abundant in patients who required ventilation, and highest in the three study participants who eventually died from COVID-19. In the laboratory, neutrophils from patients with COVID-19 churned out exceptionally high levels of NETs. Healthy neutrophils behaved the same way when they were exposed to plasma from patients with the illness. When the researchers examined the lungs of the patients who died, they found tiny clots of tangled NETs and blood platelets known as microthrombi scattered through the tissue.

Photomicrographs of human lung tissue taken from a patient who died of COVID-19. These are examples of the neutrophil extracellular trap (NET) structures associated with small blood clots. Small blood vessels are outlined with yellow dotted lines, and NETs are identified by the presence of neutrophils (in gray), altered DNA-associated proteins (green). Platelets in the blood clots are in red. Blue color stains DNA in all cells. [Xue-Yan He and David Ng, Egeblad Lab/Cold Spring Harbor Laboratory]
“This study tells us about a potential mechanism for lung injury in COVID-19 that had not previously been recognized as a possible target for treatment,” said Elizabeth Middleton, MD, the study’s first author and a critical care specialist at U of U Health. “NET levels in the blood could help predict disease severity and mortality in COVID-19,” added Christian Con Yost, MD, the study’s co-senior author and a physician-scientist at U of U Health.

The investigators also reported that a small protein found in umbilical cord blood of newborn babies, called neonatal NET Inhibitory Factor (nNIF), quiets the hyperactive NET response in white blood cells treated with COVID-19 patient plasma. This peptide is thought to protect babies from harmful inflammation early in life, explained Joshua Schiffman, MD, the study’s other co-senior author, U of U scientist, and CEO of PEEL Therapeutics. His company is now evaluating whether the protein could become the basis for a clinical treatment.

“Newborn babies have a natural therapeutic in their blood to protect against these same inflammatory events that we think could be killing COVID-19 patients,” Schiffman explained. “This targeted approach to stopping NETs may be more effective with less side effects than some other drugs being tested now in COVID-19 patients that block the entire immune system.”

Although further studies will be required, the NET-inhibitory protein may block exaggerated NET formation in COVID-19 patients,” noted Yost, whose laboratory at the U of U Health discovered nNIF in 2016. Yost also indicated that larger studies need to be performed to determine whether NETs could become a biomarker for COVID-19 severity. “We think exaggerated NETs could be a cause of morbidity and mortality in COVID-19,” he suggested.

The implications of the new NET findings extend beyond COVID-19, indicated Mikala Egeblad, PhD, a study co-author and a cancer researcher from CSHL. “Excess NETs are formed in other viral diseases,” she said. “We also know that clotting is a major cause of death in people with end-stage cancer, so what we are learning in COVID-19 may help us understand basic properties in cancer and other diseases.”

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