A 2022 study by Ohio State University (OSU) researchers suggesting that blocking a single molecule could protect against severe illness from infection with the SARS-CoV-2 virus has now led to a $15 million grant from the National Institutes of Health (NIH) aimed at finding ways to combat the effects of long COVID. The five-year grant, the largest of its kind for infection disease research received at the school, will allow investigators at OSU to build on the finding of the role of caspase 11 on lung inflammation in mice infected with the disease.
The grant will allow the researchers to extend beyond their original findings that caspase 11 sparks inflammation, worsens tissue damage and promotes blood clot formations in the lungs, as well as their discovery that the human version of the enzyme, caspase 4, was highly expressed in patients hospitalized in intensive care units.
Moving beyond the lungs, the investigators believe they will find that caspase 11 affects a variety of cell types and is a culprit in spreading inflammation through the body, including the brain, by disrupting immune responses, and triggering clots in small blood vessels. Concurrently, the researchers will delve into how SARS-CoV-2 modifies host RNA and viral components that are critical in cellular functions and viral replication. Researchers will also examine cells that line organ surfaces and blood vessel walls—epithelial and endothelial cells, respectively—as well as RNA modifications.
“When you pull it all together, offering the scientific community a basic understanding of what happens to every cell and every organ during SARS-CoV-2 is an achievement in itself,” said Amal Amer, professor of microbial infection and immunity in Ohio State’s College of Medicine and the principal investigator on the grant.
“Once you know the mechanism, then you can design what to target, where to target it and how to target it in order to reduce the damage being done. And this is especially needed for long COVID—it may be in the brain, it may be in the muscles, it may be in anything and everything—and that’s an important aspect of the disease.”
The $15 million award is a multi-principal investigator (PI) program grant, and includes Estelle Cormet-Boyaka and Jianrong Li, experts in veterinary biosciences at Ohio State and colleagues from the Nationwide Children’s Hospital and the University of Chicago.
Cormet-Boyaka, who has a long history of studying lung biology, will manage the research of multiple cells types whose functions are negatively affected by the presence of caspase 11 during SARS-CoV-2 infection and noted: “In addition to studying mice, we’ll also be using human cell samples that enable us to dissect mechanisms at the cellular level. Having access to human primary epithelial cells is a strength because those are the cells that the virus infects first.”
By conducting different arms of research simultaneously, the Ohio state team believes it can accelerate its pace of discovery.
“Long COVID is extremely complex,” said Prosper Boyaka, chair of veterinary biosciences at Ohio State. “Having a team like this one allows us to look at those interactions and processes at the same time by experts in different fields, which makes it more likely we will capture information that would be difficult to capture otherwise. That’s why I think the outcome is likely to be more beneficial than if each project were done individually or in isolation.”
