The Long Covid Mystery Has a New Suspect

Wheezing after getting on the treadmill. Gulping down air while doing chores. Breathlessness is one of the many scary and frustrating symptoms that can linger in Covid patients months after their initial infection. But while these symptoms were a mystery at the beginning of the pandemic, scientists are slowly unraveling their causes—moving us closer to finding a treatment.

In a paper recently published in the European Respiratory Journal, researchers at the University of Manchester in the United Kingdom identified a probable culprit—immune cells known as monocytes. These squishy, blue-gray cells float through the bloodstream, looking for signs of trouble. When they encounter an invading pathogen, such as bacteria or a virus, they generate other crucial immune cells and alert the immune system to activate additional defenses. Monocytes are particularly important during lung injury. At the first sign of trouble, they move to the lungs, spawning various specialized macrophages—immune cells that eat pathogens—that become the first line of immunological defense against germs invading.

But it appears a Covid infection can really mess up how these immune cells work—meaning they “can respond abnormally to subsequent events,” says Laurence Pearmain, a clinical lecturer at the University of Manchester and coauthor of the paper. In Covid patients with lasting breathlessness after an infection, the researchers found monocytes with irregularities. Compared to healthy people, these patients had monocytes with different levels of proteins attached to them that are critical for directing the cells toward the lungs. These results, the scientists say, link abnormal monocytes with long Covid and lung injury—paving the way for potential therapies to correct the abnormalities or alleviate symptoms.

Pearmain and the team had good reason to suspect these cells. Other researchers had already found that SARS-CoV-2 affects monocytes. According to Judy Lieberman, a biologist at Harvard Medical School, in cases of severe Covid, monocytes infected with the virus often die in a way that releases lots of alarm molecules into the body, triggering large amounts of additional inflammation. “It’s like a feed-forward loop,” she says. “Once this gets going, it’s incredibly hard to control.” These results pointed to the potential role of dysfunctional monocytes in long Covid, as inflammation is known to contribute to some lasting symptoms.

Pearmain and the team decided to investigate. To figure out exactly what these cells were doing during Covid and long Covid, the scientists turned to blood sampling. Starting in the summer of 2020, across several hospitals in the UK, Pearmain and the team took blood from 71 patients during their hospital stays for Covid. Over the next few months, they also collected blood from 142 separate patients previously hospitalized for Covid, gathering samples during their follow-up visits.

The patients being followed up on had had Covid around six months earlier, and by this point after an infection, Pearmain says, you would expect any immune dysfunction caused by the virus to have settled down. Yet this wasn’t what the team was seeing. “It was obvious that a lot of people were still really struggling with breathlessness, fatigue, and a lot of the other long Covid symptoms,” he says. Specifically, 48 percent of the patients being followed up reported shortness of breath, 44 percent fatigue. The team had found a long Covid cohort to study—so it was time to take a closer look at their immune cells.

First, the team looked at monocytes gathered from the hospitalized Covid patients, or people with an active Covid infection. They found that overall, compared to healthy controls, these patients with acute Covid had monocytes with irregular amounts of proteins relating to movement and inflammation—showing that monocyte irregularity begins with the initial infection. And, once these patients were stratified into mild, moderate, and severe Covid levels, several of these markers differed in their expression between the three cohorts. This showed the scientists that there can be subtle differences in monocyte irregularity among patients infected with the same virus.

Armed with this information, the team then began to study their long Covid patients. Similar to the Covid-hospitalized patients, the long Covid group also had monocytes with abnormal amounts of proteins related to movement and inflammation. Many of the patients who had reported breathlessness and fatigue also displayed abnormalities on chest radiology scans, suggesting lung injury. When the team homed in on the subset of long Covid patients with breathlessness, they noted that one particular protein in the monocytes—a receptor called CXCR6—was increased, and that its expression was highest in those patients with abnormal scans.

According to Elizabeth Mann, an immunologist at the University of Manchester and one of the study leaders, this finding was interesting. CXCR6 is the receptor for a protein called CXCL16—the two bind together. CXCL16 is sometimes expressed in the lungs, and its levels have also been found to increase during acute and long Covid. The scientists hypothesized that, with Covid having increased CXCR6 in the monocytes, this then caused them to travel more readily toward the lungs to bind with the increased CXCL16. This, they say, may have contributed to prolonged inflammation or damage.

To test this hypothesis, the scientists took monocytes from the long Covid patients with breathlessness and placed them in the top layer of a special tissue culture plate. On the bottom of the plate, they added CXCL16. If the hypothesis was true, the scientists anticipated seeing the monocytes from long Covid patients with breathlessness moving more rapidly toward the CXCL16 on the bottom of the plate, in comparison with healthy controls. That was exactly what they saw. “This enhanced CXCR6 does actually correspond to increased migration of monocytes to the CXCL16,” Mann says.

For Mann, Pearmain, and the rest of the team, this finding gives some insight into what biologically might be contributing to long Covid symptoms like breathlessness. When the team looked at blood samples from patients who had recovered from RSV or flu, they didn’t find the increased CXCR6 on monocytes that was characteristic of long Covid patients. Mann thinks that this demonstrates how monocytes in long Covid become abnormal during the acute infection and don’t recover, meaning that they persist in being drawn into the lungs and cause inflammation. This could be what leads to something like breathlessness longer term. “You need monocyte migration to go and clear the infection,” Mann says. “Once you’ve recovered, you’d hope that it goes back to normal—but it doesn’t, it seems to just stay dysregulated.”

These findings “add more to the story that there’s this dysfunctional immune response that persists in people with Covid,” says Eric Topol, a cardiologist at the Scripps Research Institute who is unaffiliated with the study. It’s a sentiment shared by David Martinez, an immunologist at Yale University, who told WIRED that it will also be “important to validate these findings in independent and larger studies that include additional human populations, such as African American and Latin individuals, who also experience long Covid.” The patients used in Mann and Pearmain’s study were predominantly white.

The next step for the scientists will be to try to modulate some of the pathways identified in monocytes—for example, using drugs to lower CXCR6 in animal models and seeing if symptoms improve. This may well have an impact on breathlessness. However, it ultimately may take more than one drug or treatment to fully alleviate the diverse array of other long Covid symptoms that patients experience. “There appear to be different mechanisms for different symptoms,” Pearmain says. “So, I don’t think we’re going to get a magic bullet that cures long Covid by just going to one source of the problem.”

To Pearmain, their study highlights what a complex disease long Covid is—and how even between long Covid patients, there is quite a bit of variation in what people experience. Some of the patients had breathlessness while others had lingering fatigue. And alongside these symptoms, patients had different levels of lung damage and CXCR6 expression. “I think that it’s very clear from this study and others that you need to be targeting the right therapy to the right patient,” he says. “That’s where I think the future of long Covid treatments will be.”