Blocking an immune response-related enzyme is promising for preventing or treating severe symptoms of COVID-19 by reducing inflammation, tissue damage, and blood clots in the lungs, according to new research on mice.
Scientists who have long studied the functions of this molecule in bacterial infections have attributed the development of significant lung damage in infected mice to increased levels of the enzyme triggered by the invasion of the SARS-CoV-2 virus.
Versions of this enzyme exist and have similar functions in mice and humans – they are called caspase 11 and caspase 4, respectively. After finding that this molecule is an interesting therapeutic target, researchers are exploring compounds that could block its activation. safely and effectively.
The general idea is that if this molecule is not present, the mouse will do better, which means that if you target this molecule, humans should do better. »
Amal Amer, lead co-author of the study, Professor of Microbial Infection and Immunity, Ohio State University School of Medicine.
The research was recently published online in Proceedings of the National Academy of Sciences.
Amer teamed up with Ohio State Influenza and COVID virologist Jacob Yount to study the role of caspase 11 in coronavirus infection. Their laboratories have conducted a number of experiments comparing the results of COVID infection in normal mice and genetically modified mice not to produce the enzyme.
“From the first experiment, we found that caspase 11 knockout mice had less serious infections and were starting to recover in just a few days,” said Yount, associate professor of microbial infection and immunity and lead co-author. of the study.
Previous research has shown that caspase 11 in mice has several of the same immune response functions as caspase 4 in humans. In both species, the enzyme is produced from the onset of an infection.
This study supports the idea that what was observed in mice is relevant to humans: Researchers analyzed nationally available data on patients with COVID-19 disease and found that caspase 4 was highly expressed in inpatients in intensive care – linking its presence to the severity of the disease. Lung tissue samples from COVID-19 patients also showed strong activation of the molecule.
The sickest COVID-19 patients develop acute respiratory distress syndrome as a result of a combination of high levels of pro-inflammatory proteins called cytokines, an accumulation of fluid in the air sacs that seeps into the lung tissue, and blood clots, or thrombosis, caused by damage to the cells lining the walls of the vessels.
In a series of experiments, the research team found that inhibition of caspase 11 reduced the intensity of multiple effects. They used a version of the SARS-CoV-2 virus that other scientists have specifically modified to cause the disease in mice. (Human coronavirus does not make mice sick).
Among the most striking results are a decrease in the recruitment and onset of inflammation of the first intervention cells called neutrophils, white blood cells whose role is to heal wounds and eliminate infections – they are important, but tend to perpetuate inflammation that damages tissues and contributes to the formation of blood clots. A technique used to visualize the smallest capillaries in the lungs of mice also showed that if the blood vessels in the lungs of normal mice infected with the virus were stained with clots, the capillaries of mice lacking caspase 11 showed no thrombosis.
“What happens in the lungs with COVID may be worse than with other infections.” It is amazing that caspase 11 controls many of these unique aspects of COVID-19 pathology, ”Yount said.
Amer said the research has opened up new avenues for thinking about the possible role of the enzyme in a multitude of diseases. Its role in exacerbating lung damage in COVID-19 disease was an unexpected discovery – the activation of caspase 11 and caspase 4 in bacterial infections has a protective function, allowing immune cells to kill bacterial pathogens. .
Caspase 11 is known to need the help of a specific protein called gasdermin-D to fight bacterial infections, but this work has shown that the enzyme intensifies lung damage during COVID-19 infection. without resorting to gasdermin-D. The link to blood clotting also suggests that the effects of caspase 11 in the presence of an infection are unlikely to stop in the lungs and can affect diseases of the heart, brain and other parts of the body.
“We’ve found that caspase 11 has other pathways, and we’re studying the function of caspase 11 in all the types of cells that cause thrombosis,” she said.
Meanwhile, Amer’s lab is already testing a caspase 11 inhibitor that it says could become a candidate drug for humans.
“The molecule has been found to inhibit thrombosis, inflammation and cytokine secretion, and it also inhibits caspase 11,” she said. “No one had shown that inhibition of caspase 11 had an effect on these downstream problems. This caspase inhibitor may well save the day. »
This work has been supported by grants from the National Institutes of Health, the American Lung Association, the Cystic Fibrosis Foundation, and the Ohio State Department of Infection and Microbial Immunity, as well as a distinguished university scholarship. of Ohio State.
Eltobgy, MM, et al. (2022) Caspase-4/11 exacerbates the severity of the disease in SARS-CoV-2 infection by promoting inflammation and immunothrombosis. PNAS. doi.org/10.1073/pnas.2202012119.