Overactive Immune Cells May Contribute to Covid Deaths

An immune system in hyperdrive may be behind some of the worst Covid-19 cases.

Part of the body’s immune system, neutrophils detect bacteria and can expel their DNA (see arrows) to attack the bacteria with a gauzy web of DNA laced with toxic enzymes, called a NET. (Picture Credit: Egeblad lab / CSHL)

(CN) — Researchers may be zeroing in on a culprit causing the most severe Covid-19 cases: overactive white blood cells which, in a Spiderman-like web attack to rid the body of unknown pathogens, could be damaging the lungs and other organs in the process.

In a paper published Wednesday in the Journal of Experimental Medicine, a group of 11 international medical research organizations hypothesized the worst cases of Covid-19, which lead to invasive mechanical ventilation and a high number of deaths, could result from the presence of overactive white blood cells called neutrophils.

Patients with the most severe Covid-19 infection develop Acute Respiratory Distress Syndrome (ARDS), pulmonary inflammation, thick mucus secretions in the airways, extensive lung damage and blood clots.

Those symptoms could be exacerbated or caused by the neutrophilic white blood cells, which, when trying to rid the body of bacteria or pathogens, expel a gauzy web of DNA laced with toxic enzymes, called a neutrophil extracellular trap or NET.

The NETs can attack and digest unwanted pathogens, but in the process may cause cases of ARDS, damaging the lungs and other organs.

A YouTube video by Cold Spring Harbor Laboratory shows how neutrophils patrol the lungs to protect people from airborne pathogens:

But during an increased immune response, the white blood cells create toxic NETs to neutralize invaders.

NETs make breathing more difficult and can cause the need for ventilation.

“Given the clear similarities between the clinical presentation of severe COVID-19 and other known diseases driven by NETs, such as ARDS, we propose that excess NETs may play a major role in the disease,” Betsy Barnes, Ph.D. in medicinal chemistry, lead and co-corresponding author of the paper and professor at the Feinstein Institute, said in a statement.

“As samples from patients become available, it will be important to determine whether the presence of NETs associates with disease severity and/or particular clinical characteristics of COVID-19,” she said.

First identified by scientists in 2004, NETs are still largely unknown by many in the scientific research community.

But researchers who have worked on NETs in other diseases noticed similarities in symptoms experienced by Covid-19 patients, according to Cold Spring Harbor Laboratory cancer biologist Mikala Egeblad.

Egeblad coalesced the NETwork research group working on Covid-19. Researchers at 11 NETwork institutions are pursuing studies into whether NETs are a common feature in Covid-19 cases. If they find excess NETs cause the severe symptoms of Covid-19, new treatments can be utilized to help patients recover.

Current treatments utilized to manage other NET and neutrophil-driven diseases including cystic fibrosis, gout and rheumatoid arthritis might decrease the activity of NETs in coronavirus patients, reducing the need for ventilation, according to the research group.

Jonathan Spicer is a thoracic surgeon who has seen the damage caused by severe Covid-19 infections.

“We see in these patients severe lung damage known as ARDS, another serious problem caused by excess NETs and seen in cases of severe influenza,” Spicer said.

“In addition, 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. NETs have also been found in the blood of patients with sepsis or cancer, where they can facilitate the formation of such blood clots.”

In an email, Engeblad said there are a lot of more of the neutrophils in Covid-19 patients with severe disease than in patients with mild disease. The question researchers need to answer is if the neutrophils are creating an excess of NETs which are making coronavirus patients sicker.

“If NETs contribute to the damages seen in lungs and other organs, then blocking NETs may stop further damage, allow the organs to heal and give other immune cells the opportunity to stop the virus,” Engeblad said.

“There are drugs already being tested in clinical trials for Covid-19 that will inhibit neutrophils and NETs, and there are other drugs that may be worth testing in trials if NETs indeed contribute to severe Covid-19,” she added.

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