Scientists who have long studied this molecule’s functions in bacterial infections have found the development of widespread lung damage in mice infected with elevated levels of the enzyme. caused by the SARS-CoV-2 virus.
Versions of this enzyme exist and 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, researchers are exploring compounds that can block its activation safely and effectively.
“The whole idea is that without this molecule, mice will do better, which means if you target this molecule, then humans will do better,” said study co-author Professor Amal Amer, at Ohio State University, USA, said. of Medicine.
The study was recently published online in Proceedings of the National Academy of Sciences.
Treating COVID-19: New insights
Amer collaborated with Ohio State flu and COVID virologist Jacob Yount to look at the role of caspase 11 in coronavirus infection. Their lab has conducted several experiments comparing the outcomes of COVID-19 infection in normal mice and mice that have been genetically engineered so that they do not produce the enzyme.
“From the first experiment, we found that the knockout mice with caspase 11 were less susceptible to severe infections, and less likely to have severe infections,” said Yount, associate professor of infection and microbial immunity and co-author of the study. begins to recover after only a few days.
Previous research has shown that rat caspase 11 has many of the same immune response functions as human caspase 4. In both species, this enzyme is produced at the onset of infection.
This study supports the notion that what is seen in mice is relevant to humans: Researchers analyzed nationally available COVID-19 patient data and found that caspase 4 is expressed present high in people admitted to the ICU – link its presence to severe illness. Lung tissue samples from COVID patients also showed high activation of the molecule.
The most severely ill COVID-19 patients develop acute respiratory distress syndrome due to a combination of high levels of inflammatory proteins called cytokines, which accumulate fluid in the air sacs that seep into lung tissue and form clots. blood clots, or blood clots caused by damage to the cells lining the blood vessels. walls.
In a series of experiments, the team found that inhibiting caspase 11 reduced the magnitude of many effects. They used a version of the SARS-CoV-2 virus that other scientists had engineered to infect mice. (Human coronaviruses do not make mice sick.
Among the most striking findings: less recruitment and inflammation primer of first-responder cells called neutrophils, the white blood cells responsible for wound healing and clearing infection – they important, but tends to prolong inflammation that damages tissue and contributes to clot formation.
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 mice infected with the virus clot, the capillaries of the mice lacked blood. caspase 11 remained thrombus-free. “What happens in the lungs with COVID may be worse than with other infections,” Yount said. “It’s surprising that caspase 11 is controlling many of the unique aspects of COVID-19 pathology.”
Amer says the study opens up new ways of thinking about the enzyme’s possible role in a range of diseases. Its role in exacerbating lung injury in COVID-19 was an unexpected finding – activation of caspase 11 and caspase 4 in bacterial infections has a protective function, establishing immune cells to destroy pathogens caused by bacteria.
Caspase 11 is known to need the help of a specific protein called gasdermin-D to prevent bacterial infections, but this study shows that the enzyme enhances lung damage in the case of COVID-19 infection without use gasdermin-D. The association with blood clotting also suggests that the effects of caspase 11 in infections may not stop at the lungs, and can affect conditions in the heart, brain, and elsewhere in the body. .
“We discovered that caspase 11 has other pathways, and we are looking at the function of caspase 11 in all cell types that induce thrombosis,” she said. Meanwhile, Amer’s lab is testing a caspase 11 blocker that she believes has the potential to be a drug candidate for humans.
“This molecule has been found to inhibit thrombus formation, inflammation, and cytokine secretion, and it also inhibits caspase 11. “No one has said that inhibiting caspase 11 has an effect on this,” she said. these downstream problems. This caspase inhibitor could save time.”