Studies pinpoint immune cells and proteins linked to long COVID

Researchers at the University of Alberta have pinpointed two proteins that could serve as markers for identifying patients with long COVID—a discovery that may lead to treatments that will bring better quality of life for the millions of people suffering from the debilitating condition.

“We wanted to find out more about what is going on with long COVID to bring relief to sufferers—especially those patients with the most debilitating symptoms, a condition called chronic fatigue syndrome, which leads to extreme tiredness and other disabling symptoms,” says immunologist Shokrollah Elahi, a professor in the U of A’s Mike Petryk School of Dentistry, who led three groundbreaking studies aimed at improving our understanding of how long COVID develops and who may be susceptible.

Most people who get the SARS-CoV-2 infection feel sick for a week or two and then recover. But about 10% end up with long-term complications that can linger for months or even years. Those complications can be wide-ranging and affect all kinds of organs, with symptoms including chronic fatigue, intense pain, trouble breathing, difficulty sleeping, cardiovascular issues and cognitive problems commonly called “brain fog.”

In the first two studies, published in the Journal of Autoimmunity and Frontiers in Immunology, the researchers looked at two sets of subjects: 78 patients with severe long COVID symptoms and 58 people who were infected with SARS-CoV-2 but fully recovered without any complications.

Telltale signs

Elahi and his team looked at various immune cells and proteins in the blood of the study participants. They discovered that the long COVID group had higher levels of immune cells called neutrophils and monocytes that cause inflammation, and fewer protective lymphocytes. They also had more worn-out or exhausted killer T cells, which are a key part of the immune system’s defense against infections.

In the blood of the long COVID patients, the team also found higher levels of various proteins related to systemic inflammation—especially galectin-9 and artemin.

These two proteins could help solve the mysteries of long COVID, Elahi says, because higher levels of galectin-9 in patients are associated with increased inflammation and brain fog. In the case of artemin, higher levels are associated with widespread pain, more severe pain and cognitive impairment.

The researchers observed that galectin-9 is shed by stressed neutrophils—the most abundant white blood cells—in long COVID patients. This released galectin-9 can promote chronic inflammation by affecting various immune cells, as Elahi’s group reported in a previous study on HIV infection.

They also found that long COVID dysregulates the production of red blood cells, which results in an abundance of immature red blood cells in the blood of these patients. Normally, immature red blood cells are present in the bone marrow but not in the blood of healthy people. It is these immature red blood cells in the blood that suppress the immune system and contribute to the elevation of artemin in the plasma of long COVID patients.

Severe infection doesn’t necessarily lead to long COVID

Elahi notes that the seriousness of the initial infection does not affect the likelihood of developing long COVID. In fact, most people who end up with long COVID initially had only a mild infection that did not require intensive care or hospitalization.

The research team also found that women are disproportionately affected by long COVID and are three times more likely than men to develop the condition.

In the third study, published in The Lancet Microbe, Elahi’s team showed there are no signs of systemic SARS-CoV-2 present in the blood of long COVID patients who were examined 12 months after infection—challenging previous assertions that the virus remains present in the blood of long COVID sufferers.

So if it’s not the virus itself, what could be causing long COVID? Thanks to the information provided by galectin-9 and artemin, Elahi says he has an idea as to what is happening.

“I think that chronic inflammation in long COVID patients results in the elevation of these two proteins. At the earliest stage of disease, we know that some patients have gastrointestinal symptoms like diarrhea—but not everybody,” he points out. “I think those individuals who have gastrointestinal involvement are more likely to develop long COVID.”

The gastrointestinal problems result in damage to the intestinal tissues, along with gut leakiness. It means that if even small traces of microbes from the gut get into the bloodstream, it could result in chronic inflammation in long COVID patients. The team found elevated levels of protein markers associated with gut leakiness in these patients.

Elahi says that is actually good news, because these gut problems can be treated. “There are medications available that can be used for gut leakiness. So I think that might be a solution for long COVID patients.”

Elahi adds that in a previous study, his team discovered that some long COVID patients had a deficiency in two amino acids, sarcosine and serine, that have anti-inflammatory functions and neuroprotective effects. Both are available as food supplements that can be purchased at health-food stores or online.

“Some patients who have taken them have claimed signs of improvement.”

Elahi says the U of A, with its recognized excellence in research related to health and well-being, is a great environment in which to do his work.

“The most important thing when you want to do human studies is having resources in place, having infrastructure so you can recruit patients. In particular, Dr. Mo Osman and his team with the University of Alberta Hospital have been instrumental for clinical assessment and patient recruitment.”

Elahi is also grateful to the long COVID community on Facebook, who were helpful in identifying and getting access to patients for the studies.

“Basically, as scientists, whatever we do, we have to bring it from the bench to the bedside, to see if we can benefit patients. This is our goal.”