Study examines viral mechanisms and treatment strategies for long COVID
Amal Amer (center) is the contact principal investigator on the grant. With her are research team members (from left): Santiago Partida-Sanchez, Jianrong Li, Maciej Pietrzak, Jacob Yount, Xiaoli Zhang, Prosper Boyaka and Estelle Cormet-Boyaka.
Collaborative discovery has led an interdisciplinary team of researchers at The Ohio State University to better understand how the depletion of caspase-11, a pro-inflammatory enzyme that is activated in our cells during an infection, can help prevent the most destructive effects of COVID-19. Their findings may hold the keys to treating acute SARS-CoV-2 infections and fending off the major health issues associated with long COVID.
Amal Amer, MD, PhD, professor of Microbial Infection and Immunity and vice chair of Translational Research at The Ohio State University College of Medicine, is the contact principal investigator for a $15 million grant from the National Institutes of Health (NIH) for her team’s research, titled “Role of the non-canonical inflammasome in SARS-CoV-2-mediated pathology and coagulopathy.”
“Understanding SARS-CoV-2 infections in the brain and lungs allows us to define and design a drug to target caspase-11’s production or its action,” Dr. Amer says. “This molecule promotes inflammation, and targeting it will result in saving the body from many pathologies.”
Studies have shown that COVID patients' cells produce elevated levels of caspase-11, leading to compounding effects in multiple cells. This uptick raises inflammation levels in the body, lungs and brain, which intensifies the immune response. The NIH-funded grant will support the work of Dr. Amer’s team to inhibit caspase-11 production and develop new ways to treat acute SARS-CoV-2 infections.
The team’s research aims to protect patients from inflammation and associated pathology that can linger even after the virus has been cleared. The particular study supported by this grant combines three scientific projects and four cores — administrative, biostatistics and bioinformatics, biological reagents and infection, and cell derivation and maintenance. With such a broad scope, the study will also allow the team to explore how SARS-CoV-2 infections shape host and viral RNA modifications, which occur during gene activation and alter cell functions. This work could have implications for Alzheimer’s disease as well.
Along with Dr. Amer, Prosper Boyaka, PhD, chair of Veterinary Biosciences, and Estelle Cormet-Boyaka, PhD, and Jianrong Li, DVM, PhD, both professors of Veterinary Biosciences at The Ohio State University, serve as MPIs on the initiative and lead specific projects. The group also involves other experts from Ohio State, Nationwide Children’s Hospital and the University of Chicago.
Dr. Cormet-Boyaka is an expert in lung biology, physiology and pathology. She is overseeing research on the various cell types that are adversely affected by the presence of caspase-11 during SARS-CoV-2 infection. She says mouse models and human cell samples will be used to analyze 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,” Dr. Cormet-Boyaka says.
As a virologist, Dr. Li has more than 25 years of experience studying respiratory viruses, including coronaviruses even before the COVID-19 pandemic. He and his colleagues are mapping the RNA modifications in host cells induced by SARS-CoV-2 and developing experimental inhibitors of molecules that trigger these RNA changes. The goal is to suppress the virus’ ability to make copies of itself in infected cells.
“The two major causes of death from COVID are the cytokine storm and uncontrolled virus replication,” Dr. Li says. “If we inhibit only one of these, it’s not ideal. If we inhibit both, that can lead to a better therapeutic approach.”
Dr. Boyaka says conducting simultaneous studies on different tracks will accelerate the pace of the research. As an expert in adaptive immunity, which plays a significant role in antiviral immunity, he will provide a strategy to manage immune cells known as neutrophils to avoid exacerbated immune responses. The collective experience and well-funded resources available will allow the researchers to tackle these approaches in a very thorough, thoughtful manner.
“Having a team like this one, with long-standing collaborations, allows us to look at those interactions and processes at the same time, drawing on the expertise of researchers in different but complementary fields,” Dr. Boyaka says. “This makes it more likely we will capture information that would be difficult to capture otherwise.”
The study will last five years, but it is possible the much-needed caspase-11 inhibitor will be discovered at any time. Dr. Amer says the ability to treat patients will depend on whether an existing drug could be used to effectively target and block caspase-11 or if a new treatment will need to be developed and tested.
“We know that we don’t want high levels of caspase-11 in the body,” Dr. Amer says. “Once we identify a viable treatment that will target this enzyme, we will be able to give patients a chance to overcome the detrimental effects of the virus in the lungs and the brain and to protect against long COVID.”