The blocking an enzyme involved in the immune response could be a promising strategy to prevent or treat severe symptoms of COVID-19 by reducing inflammation, tissue damage and blood clots in the lungs, according to new research in mice published by the Ohio State University (United States).
These scientists, who have long studied the roles of this molecule in bacterial infections, have found that the development of extensive lung damage in infected mice it is due to elevated levels of the enzyme triggered by the invading SARS-CoV-2 virus.
There are versions of this enzyme that have similar functions in both mice and humans: they are called caspase 11 and caspase 4, respectively. After discovering that the molecule is an attractive therapeutic target, the researchers are exploring compounds that can safely and effectively block its activation.
“The idea is that if this molecule is not there, the mouse will be better off, which means that if it targets this molecule, humans should be better off,” explains Amal Amer, one of those responsible for the research, who has published in the scientific journal ‘Proceedings of the National Academy of Sciences’.
Caspase 11 function
Amer teamed up with Jacob Yount, a COVID-19 virologist and from the Ohio State University, to study the role of caspase 11 in coronavirus infection. His laboratories carried out a series of experiments comparing the results of COVID-19 infection in normal mice and in mice genetically modified so that they did not produce the enzyme.
“From the first experiment, we saw that the mice in the caspase 11 had less severe infections and they started to recover after a couple of days,” says Yount, a co-author of the study.
Previous research has shown that caspase 11 in mice has many of the same immune response functions as caspase 4 in humans. In both species, the enzyme is produced at the onset of an infection.
This study supports the idea that what was observed in mice has relevance to humans. The researchers analyzed data from COVID-19 patients and discovered that caspase 4 was highly expressed in hospitalized people in the intensive care unit (ICU), which relates its presence to the severity of the disease. Lung tissue samples from COVID-19 patients also showed high activation of the molecule.
Sicker COVID-19 patients develop acute respiratory distress syndrome, the result of a combination of high levels of pro-inflammatory proteins called cytokines, fluid buildup in the air sacs that seeps into lung tissue, and blood clots , or thrombosis, caused by damage to the cells lining the vessel walls.
In a series of experiments, the research team found that caspase 11 inhibition reduced the intensity of the multiple effects. They used a version of the SARS-CoV-2 virus that other scientists have specifically engineered to cause disease in mice.
Among the most surprising findings: decreased recruitment and inflammatory priming of first responder cells called neutrophils, white blood cells whose job it is to heal wounds and clear infections; they are important, but they have a tendency to perpetuate inflammation that damages tissues and contributes to the formation of blood clots.
A technique used to image the tiniest capillaries in the lungs of mice also showed that, while the blood vessels in the lungs of normal virus-infected mice were stained with clots, the capillaries of mice that lacked caspase 11 remained free of thrombosis.
“What happens in the lung with COVID-19 may be worse than with other infections. It’s surprising that caspase 11 controls so many of those unique aspects of COVID-19 pathology,” Yount says.
Amer points out that this research has opened new ways of thinking about the possible role of the enzyme in a series of diseases. Their role in exacerbating lung damage in COVID-19 was an unexpected finding: Activation of caspase 11 and caspase 4 in bacterial infections has a protective role, as it primes immune cells to kill bacterial pathogens.
It’s known that caspase 11 needs the help of a specific protein called gasdermin-D to prevent bacterial infections, but this work showed that the enzyme intensified lung damage in COVID-19 infection without using gasdermin-D.
The association with blood clotting also suggests that the effects of caspase 11 in the presence of infection are probably not limited to the lungs and may affect diseases of the heart, brain, and other parts of the body.
“We discovered that caspase 11 has other pathways, and we are studying the role of caspase 11 in all types of cells that cause thrombosis“, the researchers detail.
Meanwhile, Amer’s lab is already testing a caspase 11 blocker that he says has the potential to become a human drug candidate.
“This molecule has been found to inhibit thrombosis, inflammation, and cytokine secretion, and it also inhibits caspase 11. No one had agreed that caspase 11 inhibition has an effect on these downstream problems. This inhibitor of caspase can save the day”, emphasizes the scientist.
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