‘Spider-Man’ Immune Response May Promote Severe COVID-19

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The menagerie of immune cells and proteins that defend the human body have received mounting scrutiny in struggles to ward off COVID-19. A lot of the debate has centered around whether, after recovery, a person carrying antibodies can safely return to the workplace. But attention has also turned to runaway immune reactions provoked by the infection that can lead to respiratory failure.

One relatively obscure accomplice when the defense system goes awry is a “Cinderella” immune cell called a neutrophil. Understudied and overshadowed by virus-fighting T cells and antibody-producing B cells, neutrophils make up more than half of our white blood cells and are often the first to arrive at the scene of infection. They attack invaders in several ways—usually by gobbling the intruders up or rallying other immune cells to the fight. But occasionally, perhaps in a last-ditch defensive effort, neutrophils pull a Spider-Man maneuver: they shoot out sticky webs of DNA and toxic proteins that ensnare pathogens and prevent them from spreading. Because a neutrophil dies when it engages in this process —or shortly thereafter—some researchers consider the webs a cellular version of suicide bombing.

In a study published on April 24 in JCI Insight, scientists report finding these mysterious structures, called neutrophil extracellular traps (NETs), in serum samples from people hospitalized for COVID-19. And several groups have started recruiting patients with the disease for clinical trials of existing drugs that disrupt NETs or block their formation.

The web structures first caught scientists’ attention in 2004, when a paper in Science reported on NETs in bacterial conditions such as dysentery and appendicitis. But Andrew Weber, a pulmonary and critical care physician in the Northwell Health system in New York State knew nothing about them until he heard a local scientist give a presentation about her research last fall: Mikala Egeblad spoke about how NETs can promote the spread of cancer—a focus of her lab’s studies at New York’s Cold Spring Harbor Laboratory. And she raised the possibility that they could also play a role in vaping-associated lung injury. Pre-COVID-19, Weber says, “that was the biggest epidemic that we needed to worry about.”

Intrigued, Weber chatted with Egeblad about a possible study to look for NETs in serum samples from these patients. The two wrote a proposal and got it approved, but then the COVID-19 pandemic hit. Sidelined at home, writing research grants, Egeblad continued reading about NETs. In early March Weber started seeing the first wave of COVID-19 patients. He found their lungs clogged with thick mucus and overrun with neutrophils. And he knew, based on reports coming out of China, Italy and other hard-hit countries, that patients with high neutrophil counts tended to fare worse.

“We separately thought, This sounds like NETs,” Egeblad says. She talked with Weber and another collaborator, Betsy Barnes of Northwell Health’s Feinstein Institutes for Medical Research, about getting COVID-19 patient samples to test their hunch. A few days later, Egeblad saw a March 15 tweet by University of Michigan rheumatologist Jason S. Knight, who studies NETs in autoimmune disease.

Knight and his colleagues had also noted inflammation and high neutrophil counts in published analyses of China’s COVID-19 patients and thought, “Someone should be testing for NETs,” he says. “It seemed like such a paper would pop up any day.” Knight searched the biomedical database PubMed for “coronavirus AND neutrophil extracellular traps” and tweeted a screenshot of the results: zero. In early March, as it became clear that Michigan would be a hotspot, his team started discussing how to study NETs in COVID-19.

Then Egeblad reached out to Knight. After several Zoom calls, they and more than a dozen other scientists and physicians formed a consortium, called the NETwork, to share protocols and explore if neutrophil traps play a role in the disease.

A commentary published in the Journal of Experimental Medicine explains the rationale. In the sickest people infected with the novel coronavirus, the immune system unleashes a flurry of molecules called cytokines, some of which regulate the activity of neutrophils. These “cytokine storms” trigger acute respiratory distress syndrome (ARDS), a serious condition that develops in 10 to 15 percent of COVID-19 patients. Prior research has linked ARDS to NET formation, and compounds that degrade NETs or block their formation can relieve ARDS in mice. In people with cystic fibrosis—an inherited disease that causes persistent lung infections—a medication called dornase alfa that breaks up NETs by cleaving DNA can loosen sputum and relieve symptoms.

Indeed, in the April 24 JCI Insight study, Knight, University of Michigan researchers Yogendra Kanthi and Ray Zuo, and their colleagues detected NETs in serum samples from 50 patients with severe COVID-19 but not in healthy controls. And they showed that the infected patients’ serum could trigger NET formation by healthy neutrophils grown in the same dish.

The data confirm “that neutrophils are going to be very important in COVID-19,” says James Chalmers, a pulmonologist at the University of Dundee in Scotland. Chalmers was not involved in the new research but has studied neutrophils since 2008, when NETs “were the hot new thing,” he says.

Chalmers is leading a clinical trial that will enroll COVID-19 patients to test a daily pill that blocks the activity of neutrophil enzymes that are needed for NET formation. In a recent study by the global pharmaceutical company Insmed, which is funding the new trial, this drug reduced inflammation in people with a chronic respiratory condition called bronchiectasis. Starting in May, Chalmers’s investigation will recruit 300 people from 10 hospitals across the U.K. to receive either the drug or a placebo. Additional trials are testing other NET-targeting agents —such as dornase alfa and drugs approved for rheumatoid arthritis and gout—in patients hospitalized for COVID-19.

NETs have been somewhat of a fringe topic because they are rare and hard to detect in the lab. Also, because neutrophils die when they carry out the web-shooting defensive mission, it is difficult to know what really happened after the process has occurred. “Did the cells die on purpose, or did I accidentally kill the cells when I was working with them?” Chalmers asks.

Plenty of evidence suggests an association between NETs and the cytokine storms seen in severe cases of COVID-19. But “we don’t have that proof yet,” Egeblad says. In future analyses of patient samples, “we need to measure NETs and measure cytokines and see who comes first and if they are linked,” she adds. The researchers also plan to study how neutrophils communicate with another type of immune cells called macrophages, which can exacerbate or tamp down lung inflammation.

Meanwhile scientists are also unsure if NETs are, in fact, harmful or if they could be doing something useful. Paul Kubes, an immunologist at the University of Calgary in Alberta, who is not involved with the NETwork, suspects the structures are produced for a good reason—to help us fight infection—but may “go rogue.” The new coronavirus, he adds, “might be clever enough to make use of that and make us sick.” Whatever the true role of NETs as immunological combatants, the urgency of the pandemic seems to be lifting neutrophils out of obscurity and prompting a close look at their bizarre, protruding webs of DNA.

Read more about the coronavirus outbreak here.



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