A $15 million federal grant from the National Institutes of Health (NIH) was awarded to Ohio State University and will help fund the institution’s pursuit of definitive answers and development of new ways to treat acute SARS-CoV-2 infections and, ideally, fend off long COVID. The award aimed for 5 years of research is the largest of its kind funding infectious diseases research at Ohio State.1
“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, MD, PhD, professor of microbial infection and immunity in Ohio State’s College of Medicine and the contact principal investigator on the grant.1
The grant stems from previous research done in animal studies. In 2022, Ohio State investigators examined infected mice with SARS-CoV-2 that blocked an enzyme called caspase 11, that resulted in lower inflammation and tissue injury and fewer blood clots in the animals’ lungs. Additionally, the investigators found that the human version of the enzyme, called caspase 4, was highly expressed in COVID-19 patients hospitalized in the ICU, thus confirming the molecule’s link to severe disease.1
What You Need to Know
A $15 million federal grant from the NIH has been awarded to Ohio State University to fund research aimed at developing new treatments for acute SARS-CoV-2 infections and long COVID.
Previous research by Ohio State investigators identified the enzyme caspase 11 (in mice) and its human homolog caspase 4 as key players in severe COVID-19 cases. Inhibiting these enzymes was shown to reduce inflammation, tissue injury, and blood clots in infected mice.
The NIH grant will support research beyond lung effects, examining how caspase 11 influences inflammation in various cells and its role in RNA modifications during SARS-CoV-2 infection.
Their research was published in the Proceedings of the National Academy of Sciences in May 2022. In the study, the investigators discussed the potential molecule and why it should be further examined. “Our findings collectively suggest that targeting the CASP11 homolog, human CASP4, during COVID-19 will prevent severe pneumonia, inflammation, tissue damage, and thrombosis as well as accompanying repercussions such as low oxygen, lung failure, need for ventilators, and possibly long-term sequelae. These advantageous effects will be achieved without compromising viral clearance. Targeting CASP4 alone may achieve benefits that exceed and replace the administration of a large number of individual anti-inflammatory agents and antithrombotics given to SARS–CoV-2 patients,” the investigators wrote.2
The NIH grant will examine beyond the lungs based on predictions that in response to the viral infection, caspase 11 has compounding effects in multiple cells: driving up inflammation in the body and brain, interfering with the immune response and leading to clots in small blood vessels. The team will also explore how SARS-CoV-2 infection shapes host and viral RNA modifications, which occur during gene activation and alter cell functions. Many of the affected cells being investigated are related to the immune response—both the innate response, the body’s first line of defense against any foreign invader, and the adaptive response, which is a later, specific response to a given pathogen. Researchers will also examine cells that line organ surfaces and blood vessel walls (epithelial and endothelial cells, respectively) as well as RNA modifications.1
“When you inhibit caspase 11, you get rid of many cytokines, which damage the lung tissue and the blood-brain barrier and brain tissue,” Amer said. “Combining that together with stopping viral replication is going to be very effective at reducing deaths and severe illness from SARS-CoV-2 infection, and reducing the post-infection symptoms experienced by people with long COVID.”1
One of the other primary investigators, Jianrong Li DVM PhD, professor of veterinary biosciences, Ohio State University will map SARS-CoV-2-induced RNA modifications in host cells and work on experimental inhibitors of molecules that trigger the RNA changes as a strategy to suppress the virus’s ability to make copies of itself in infected cells. The team will develop and test RNA modification and caspase 11 blockers to synergistically reduce SARS-CoV-2 replication, pathology and clotting, protect tissue and prevent the over-production of pro-inflammatory proteins called cytokines.1
“The 2 major causes of death from COVID are the cytokine storm and uncontrolled virus replication,” Li said. “If we inhibit only one of these, it’s not ideal. If we inhibit both, that can lead to a better therapeutic approach.”1
References
1. Finding a solution for long COVID, one cell type at a time. EurekAlert. July 23, 2024. Accessed July 29,2024.
https://www.eurekalert.org/news-releases/1052300
2. Eltobgy MM, Zani A, Kenney AD, et al. Caspase-4/11 exacerbates disease severity in SARS-CoV-2 infection by promoting inflammation and immunothrombosis. Proc Natl Acad Sci U S A. 2022;119(21):e2202012119. doi:10.1073/pnas.2202012119
