Even at the very beginning of the pandemic, doctors found that the risk group includes people with vascular diseases, the elderly, and diabetics.
The body of people with obesity and diabetes can not cope with the processing of incoming glucose. In the blood of these people, it is more than usual. A cohort study of 7,000 people found an addiction. Uncontrolled blood glucose levels increase the mortality and severity of COVID-19.
Brazilian scientists have studied the mechanisms of this dependence. They found how glucose levels affect the reproduction of the coronavirus.
The energy metabolism metamorphoses
The severe form of COVID-19 is associated with lung damage. Accumulate in the lung cells of the immune system to fight infection. Monocytes are the most active cells of the immune system. Nevertheless, the virus gets into them, infects them, and uses them for its reproduction. Infected monocytes produce many signaling proteins that increase inflammation and tissue damage.
Scientists observed monocytes infected with coronavirus in the laboratory. Monocytes were taken from people with obesity and diabetes. The researchers used three levels of glucose concentration to model different physiological States.
Scientists have found that glucose directly contributes to the reproduction of the virus. Glucose also increases the production of pro-inflammatory signaling proteins by monocytes. Moreover, these processes intensified as the concentration of glucose increased.
Cells use glucose oxidation-glycolysis-to generate energy. Brazilian scientists have analyzed 144 proteins associated with carbon and energy metabolism. The researchers observed the activation of several genes associated with glycolysis in an environment with a maximum glucose concentration. As a result, it was found that the virus stimulates glycolysis in monocytes and increases their glycolytic capacity.
For comparison, the researchers conducted similar experiments with the respiratory syncytial virus (RSV) and H1N1 influenza A virus (IAV). For these viruses, the increase in glucose concentration did not cause increased glycolysis. Therefore, the scientists concluded that high glycolysis in monocytes is specific for SARS-CoV-2.
The importance of the oxidation of glucose for the reproduction of coronavirus
Scientists continued to study the role of glucose in the development of the disease. They used a drug that suppresses glucose uptake. As a result, the drug completely stopped the reproduction of the virus in infected monocytes. At the same time, monocytes stopped producing additional pro-inflammatory proteins in comparison with healthy monocytes.
In another group of infected monocytes, a drug that stimulates glucose uptake was used. In this case, the study has observed the opposite effect of increased reproduction of the virus and the production of Pro-inflammatory proteins.
This experiment demonstrates that carbon is necessary for the coronavirus to reproduce. Also, carbon that is not associated with respiration is needed by monocytes to show a reaction to the coronavirus.
In the next experiment, the researchers observed the effect of other carbon sources on the metabolism of infected cells. In addition to glucose, galactose and pyruvate were used. Galactose inhibits aerobic glycolysis – glycolysis with the participation of oxygen. In this case, the cells have to rely on a less efficient energy production process – oxidative phosphorylation. Pyruvate is the result of glucose processing during glycolysis.
The coronavirus only propagated in the presence of glucose or glucose with pyruvate. However, RSV and IAV viruses could also multiply in the presence of galactose and a drug that blocks glucose uptake.
Continuing the experiment, the scientists used a drug that suppresses the activity of mitochondria – the energy centers of the cell. The drug did not affect the reproduction of coronavirus in infected monocytes. Thus, scientists have proved that the glycolytic flow is not only necessary but also sufficient for the virus to reproduce.
To clarify the revealed dependence, a drug that reduces the rate of glycolysis in monocytes was used. In this case, the rate of reproduction of the virus also decreased.
Completing this cycle of experiments, the scientists used a drug that blocks aerobic glycolysis. The drug stopped the virus from multiplying and reduced the production of pro-inflammatory proteins.
Thus, scientists have demonstrated that the reproduction of coronavirus occurs due to aerobic glycolysis.
The effect of coronavirus on the metabolism of monocytes
In previous experiments, a direct relationship was established between the concentration of glucose and the rate of virus reproduction. Moreover, the reproduction of the virus required the oxidation of glucose with the participation of oxygen.
So in the next step, the scientists studied the respiratory capacity of infected monocytes of how the coronavirus changes the metabolism of monocytes to get the right amount of oxygen. In a series of experiments, the researchers compared the indicators of infected monocytes with those of healthy ones.
First, it was found that the genes responsible for oxygen levels are more active in infected monocytes. To get more detailed information, scientists used drugs that affect the activity of these genes.
The drug, which suppresses the activity of genes, led to a decrease in the concentration of the virus. The drug also prevented the increased synthesis of pro-inflammatory proteins.
The drug, which stabilizes the activity of genes, had the opposite effect. It increased the viral load. Furthermore, infected monocytes began to produce pro-inflammatory proteins more actively, exacerbating the inflammatory condition.
At the next stage, scientists studied the mechanisms of activation of these genes. It is known that their strong inducers are reactive oxygen species. Sources of ROS are mitochondria – they undergo oxidative processes, generate heat and electrical potential.
Brazilian scientists have found the disruption in the electron transport chain on the inner membrane of mitochondria in infected monocytes. This disorder reduced the respiratory capacity of the monocytes. The researchers also noticed that in infected monocytes, oxidative stress was accompanied by increased production of reactive oxygen species.
In the final step, the researchers used mitochondrial antioxidant drugs. The goal was to prevent oxidative stress and prevent reactive oxygen species from leaving the mitochondria and entering the cytoplasm of monocytes. The use of drugs stopped the virus from multiplying and prevented the production of additional pro-inflammatory proteins.
Infected monocytes reduce antiviral immunity
T-lymphocytes are the special cells of the immune system to detect and destroy the virus.
T-lymphocytes are the central part of antiviral immunity. They cleanse the body of all genetically alien objects and destroy the body’s infected cells.
Scientists have studied the effect of infected monocytes on the reproduction of T-lymphocytes. To do this, the researchers grew T-lymphocytes together with monocytes infected with the coronavirus. The culture medium for the cells contained a high concentration of glucose.
As a result of the experiment, scientists observed a reduced reproduction of T-lymphocytes. The level of the t-lymphocyte depletion marker also increased. Moreover, the T-lymphocytes themselves produced fewer immunomodulatory proteins.
The scientists then added a mitochondrial antioxidant drug to the cells. It restored the reproduction of T-lymphocytes, reduced the marker of t-lymphocyte depletion, and increased the production of immunomodulatory proteins.
These data explain the cause of severe forms of COVID-19 in patients with high blood glucose levels. These patients often have an increased viral load and lymphopenia – a decrease in the concentration of T-lymphocytes.
Infected monocytes cause the death of lung epithelial cells
Monocytes infected with coronavirus produce additional pro-inflammatory proteins.
Scientists have studied how infected monocytes affect the cells of the lungs. The lung epithelial cell culture was treated with infected monocytes. The result was the death of epithelial cells.
Then the scientists added a drug that suppresses the activity of genes that regulate oxygen levels. The drug stopped cell death.
Scientists have concluded that high glucose levels and the production of reactive oxygen species by mitochondria contribute to the death of epithelial cells in coronavirus.
Conclusions
Increased glucose levels directly increase the viral load in COVID-19. Glycolytic flow is necessary for the coronavirus to reproduce. Coronavirus affects the production of reactive oxygen species by mitochondria. Infected monocytes contribute to the death of lung epithelial cells and t-lymphocyte dysfunction.
The findings demonstrate why uncontrolled diabetes contributes to severe COVID-19. Treatment aimed at suppressing glycolysis and ROS production may be relevant.
