Casting NETs in SARS: Overactive Neutrophils in COVID-19

Investigators suspect that an underrecognized, but potent immune system defense could underlie the lung damage and thrombosis in patients with coronavirus disease 2019 (COVID-19). This defense ensnares pathogens in neutrophil extracellular traps (NETs) and could provide new targets for therapeutic intervention.

"We propose that the exacerbated host response in patients with severe COVID-19 centers around the aberrant activation of the most common leukocyte in peripheral blood, the neutrophil," Betsy Barnes, PhD, from the Institute of Molecular Medicine, Feinstein Institutes for Medical Research, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell and colleagues stated in a paper published in the Journal of Experimental Medicine.

Barnes and colleagues from an international consortium of 11 research institutes called the "NETwork", have spent several years studying the more familiar mechanisms of oxidative burst and phagocytosis that neutrophils deploy against pathogens and examining the formation of NETs in different disease states, including acute respiratory distress syndrome (ARDS).

The investigators describe the NETs as web-like structures of DNA and proteins expelled from the neutrophil that ensnare pathogens. "Expelling DNA to the extracellular space is not widely recognized as a critical immune function," Barnes and colleagues pointed out.

"Most of the researchers in the NETwork have worked on NETs in other diseases, and when we started hearing about the symptoms of the COVID-19 patients, it sounded familiar," Mikala Egeblad, PhD, of Cold Spring Harbor Laboratory, the senior author of the paper, recounted in a statement released at the time of the publication.

Egeblad, a cancer biologist, is credited for alerting the NETwork research group to the possible relevance of NETs to COVID-19 and encouraging examination of mechanisms linking NETs to the extensive lung damage and microthrombosis that characterize severe, late stage COVID-19.

A NETs-related pathology underlying the most severe presentations of COVID-19 was a striking possibility for Jonathan Spicer, MD, PhD, a clinician scientist at the NETwork affiliated Research Institute of the McGill University Health Centre, and a thoracic surgeon who has encountered ARDS in these patients.

"...their airways are often clogged with thick mucus and unlike most severe lung infections, these patients tend to form small clots throughout their body at much higher rates than normal," Spicer related in the statement. "NETs have also been found in the blood of patients with sepsis or cancer, where they can facilitate the formation of such clots."

Barnes and colleagues pointed out that NETs are formed in a regulated process that—although incompletely understood—could offer targets for interruption. Key enzymes in the formation of NETs include neutrophil elastase (NE), which degrades intracellular proteins and triggers nuclear disintegration; peptidyl arginine deiminase type 4 (PAD4), which citrullinates histones to facilitate decondensation and release of chromosomal DNA; and gasdermin D, which generates pores in the membrane of the neutrophil, facilitating cell membrane rupture and the expulsion of DNA and associated molecules.

The actions of the NETs are similarly complex, but open further possibilities for interruption. The NETs could interact with the "cytokine storm" found in severe COVID-19, for example, as they have been found to induce macrophages to secrete IL1ß, which, in turn, enhances further NET formation in various diseases, including severe asthma.

"Together, these data suggest that under conditions in which the normal signals to dampen inflammation are lost, such as during a cytokine storm, a signaling loop between macrophages and neutrophils can lead to uncontrollable, progressive inflammation," Barnes and colleagues indicated.

There are already drugs available or in development which target NETs, the investigators point outed. The NE inhibitor, sivelestat, for example, is approved to treat ARDS in Japan and South Korea, although a meta-analysis of clinical trials did not find that it increased survival. A new generation of NE inhibitors currently in phase 1 testing which could prove more effective include lonodelestat, alvelestat, and elafin.

The investigators also suggested the possibility of "repurposing" currently approved agents that could exert actions on NETs. Disulfiram, used to treat alcoholism, for example, has been reported to inhibit gasdermin D and reduce lung injury in animal studies; and the anti-gout agent, colchicine, acts to inhibit neutrophil recruitment to sites of inflammation, as well as inhibit secretion of IL1ß.

"Though treatments targeting NETs would not directly target the SARS-SoV-2 virus, they could dampen the out-of-control host response, thereby reducing the number of patients who need invasive mechanical ventilation, and importantly, reducing mortality," Barnes and colleagues posited.