Scientists have identified another cause of the cytokine storm in Covid-19

Scientists have identified another cause of the cytokine storm in Covid-19
Scientists have identified another cause of the cytokine storm in Covid-19

Canadian scientists have found that patients with coronavirus have significantly increased levels of the protein galectin-9 in the blood plasma. They also found a correlation between Gal-9 concentrations and pro-inflammatory cytokines, the release of which leads to a cytokine storm.

Field Hospital for Coronavirus Patients

While the majority of those infected with the coronavirus are asymptomatic or only mildly symptomatic, others are severely ill and need to be hospitalized. In patients who have been admitted to hospitals due to Covid-19, acute respiratory distress syndrome is a common complication - a serious manifestation of respiratory failure, accompanied by noncardiogenic pulmonary edema, respiratory distress and hypoxia. As a result, multiple organ failure may develop and death may occur.

Although the mechanism of lung damage and multiple organ failure in coronavirus infection is not well understood, the cytokine storm is believed to contribute to the pathogenesis of Covid-19. Hypercytokinemia is a rapid proliferation and increased activity of T cells, macrophages and natural killer cells with the release of various inflammatory cytokines and chemical mediators by protective cells. In general, it seems that viral load, accompanied by dysregulation of the innate immune response due to various factors, including aging, can cause a cytokine storm.

Scientists from the University of Alberta (Canada) have proposed another reason for this dangerous condition. As described in a study published in the journal mBio, they identified a protein in the blood that is responsible for "cytokine release syndrome." It was galectin-9 (Gal-9): it binds to carbohydrates and proteins and is widely expressed in the cell nucleus, its cytosol, outer plasma membrane and extracellular matrix. Gal-9, like other members of the β-galactoside-binding protein family, is synthesized on free polysomes in the cytoplasm and secreted in nonclassical ways or is freely released after cell death. Galectins are involved in many biological functions such as development, signaling, and immune responses.

By interacting with its receptors, galectin-9 exhibits various, sometimes opposite effects. So, it causes chemotaxis (a motor reaction of freely moving cells towards or away from a chemical stimulus), enhances the secretion of cytokines by mast cells, and also promotes the maturation of dendritic cells. At the same time, galectins regulate the innate immune response. For example, last year, researchers examined the role of galectin-3 inhibitors in reducing hyperinflammation in coronavirus.

However, the function of Gal-9 in Covid-19 patients remained poorly understood. Therefore, the authors of the new work decided to measure the concentration of this protein in the blood of 120 infected with SARS-CoV-2 and compare with the control, healthy group (59 people), as well as HIV-infected and people with virus-associated tumors (161 people).

“We found higher plasma Gal-9 levels in Covid-19 patients compared to healthy people who had between zero and 2042 picograms of the substance per milliliter. Also, the concentrations of galectin-9 were significantly higher in seriously ill patients (from 1950 to 125,510 picograms of substance per milliliter) compared with patients with mild / moderate disease (from 1000 to 83,717 picograms of substance per milliliter).When we compared Gal-9 indicators in men and women, there was no significant difference, it did not depend on age either. Analysis of 30 cytokines and chemokines showed a positive correlation of plasma Gal-9 with C-reactive protein and pro-inflammatory cytokines / chemokines such as interleukin-6, tumor necrosis factor alpha (TNF-α), IP-10, MIP-1α and MCP- 1, but was inversely correlated with transforming growth factor β (TGF-β) in patients with coronavirus,”the researchers said.

They then collected blood from some patients at different points in time over the course of 21 days: plasma protein concentrations gradually decreased as they recovered. Considering the difference in galectin-9 indices in sick and healthy people, as well as in people with HIV and cancer, scientists assumed that it could be used as a marker for detecting coronavirus (Gal-9 levels below 2042 picograms of substance per milliliter are normal for those with no Covid-19).

According to scientists, galectin-9 "trains" immune cells to produce and quickly release pro-inflammatory cytokines in response to SARS-CoV-2. And because inflammation damages tissues, more Gal-9 is released from the cells, thus starting a vicious circle. Even if sufferers survive the cytokine storm, the dysregulation of the immune system will lead to conditions known as prolonged Covid-19 and post-covid.

Now we need to develop methods that will block or inhibit the production of galectin-9. Although lactose or anti-Gal-9 antibodies are already known to help with this, there are no drugs on the market that are suitable for treatment. “We will expand the study to a large cohort of participants, and then we will validate our concept in animals. Covid-19 patients are often killed not by the virus, but by the cytokine storm. Therefore, if it is possible to minimize the effect of the cytokine storm by inhibiting galectin-9, it will be possible to avoid complications by lowering the number of hospitalizations and mortality rates.”

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