Understanding immunity is a matter of the heart

U of A researcher awarded CIHR Early Career Investigator Award in Circulatory and Respiratory Health

Kirsten Bauer - 26 June 2020

Immune cells in the heart play a key role in our ability to resist viral infection, according to Xavier Clemente-Casares, assistant professor in the Department of Medical Microbiology and Immunology and member of the Li Ka Shing Institute of Virology, Women and Children's Health Research Institute (WCHRI) and the Cancer Research Institute of Northern Alberta (CRINA).

Clemente-Casares, who joined the University of Alberta in the summer of 2019, is the recipient of a prestigious Canadian Institute of Health Research (CIHR) Early Career Investigator Award in Circulatory and Respiratory Health. Having recently added the final touches to his new laboratory, he is eager to roll up his sleeves and get to work on his latest research on viral myocarditis.

"As a lab we are still very new, but the research on viral myocarditis and infection is not," said Clemente-Casares. "It's been going on for many years, but because of the new technological advances that allow us to isolate specific immune cells from the heart, many new kinds of analyses are now possible that will allow us to dig deeper than before."

Myocarditis refers to inflammation in the heart tissue that affects the heart's ability to function, and in severe cases can lead to adverse effects including blood clot, stroke and heart attacks. In a condition known as viral myocarditis, when myocarditis is triggered by a viral infection, the body's immune response is activated by cells in the heart in order to fight off the infection.

In some cases, the immune response is either insufficient or too aggressive, furthering the long-term negative effects on sick patients. Clemente-Casares hopes that his research could eventually lead to the discovery of biomarkers that could help understand why this happens, in order to prevent and treat myocarditis. Read his explanation in the Q&A below.

Q: What is your research focus?

A: In heart disease, resident and recruited immune cells perform many tasks that determine the way the disease is going to evolve. An example of this is viral myocarditis. In a recent study published in Immunity, we identified a subtype of cardiac resident immune cell, called a dendritic cell, that is essential to prevent permanent heart damage caused by a viral infection. These dendritic cells specialize in virus detection, and they inform other immune cells, called lymphocytes, that there is an infection that has to be contained.

Lymphocytes are the 'warriors of the body' that help fight off infections. Having learned that, we are now focusing our research on the functions of a subset of lymphocytes, called CD4 T cells. These cells determine the best strategy to fight infections, and tell the other cells when to act. There are many kinds of cells that might be responsible for that, but CD4 T cells are very well positioned to send signals to other immune cells.

In some cases, the lymphocytes make the wrong decision, and they are not able to stop the infection, because the virus has already spread too much, or they can become too aggressive and turn against their own body. What we are trying to identify are these critical steps in the decision-making process that signal a balanced response. This will help us to understand what causes an appropriate immune response versus too much or too little, resulting in adverse patient outcomes.

Q: How do you think this will affect the way we treat diseases?

A: These studies can be related to any kind of infection. The reason why some people progress to very severe infection symptoms rather than experiencing a full recovery is linked to the way the immune system responds to that infection. A good example is the current COVID-19 crisis. It's quite clear that there is a subset of patients who develop very severe symptoms, and this is associated with an overactive immune response. In these instances, the administration of drugs commonly used to dampen an immune response, such as therapies for arthritis and other autoimmune diseases, is showing some benefits.

Q: In a perfect world, what would be the outcome of this research?

A: Some patients develop myocarditis and they just recover. Often, they don't even know they have it. But there's a significant proportion of patients that have had viral myocarditis who end up developing cardiac complications later on that can lead to death, and we don't know why.

In cases where the immune response is too strong, these complications can be treated with immunosuppressants. In contrast, other patients whose immune response is not strong enough benefit more from antiviral therapy. We believe that by studying the signals that determine whether you're mounting the right kind of immune response, we may be able to find biomarkers that tell us where the balance is tipping. This gives us the opportunity for personalized intervention, if necessary, to prevent further heart complications.

Q: Are there particular demographics that are affected by viral myocarditis?

A: While symptomatic myocarditis is a rare disease, the real incidence of its silent form is unclear. For instance, some studies are showing that up to 20 per cent of sudden-death cases in young adults are linked to myocarditis. Unfortunately, in many cases, this is usually diagnosed post-mortem, so we don't really have an accurate picture until we do a proper biopsy.

One thing we do know is that viral myocarditis is extremely severe in children, with a high rate of mortality or long-term effects. The reason for this is unclear, and it is another aspect of the disease that we are trying to unravel within our myocarditis research program.

Q: Why did you choose to come to the U of A?

A: The U of A is home to globally renowned cardiology and virology programs. Also, as a member of the Li Ka Shing Institute of Virology, I am in close collaboration with a great group of interdisciplinary researchers building a scientifically stimulating research environment. On top of that, our research is well supported by state-of-the-art facilities and services. We've been working on bringing people together to collaborate here, including cardiology researchers, and I'm hoping the U of A can become a multi-disciplinary hotspot for viral myocarditis research.

Q: What does the Early Career Investigator Award signify to you?

A: This is a very prestigious award, so it is very encouraging. Aside from the recognition of the work that has already been done, this award comes with some financial support. It demonstrates that there is interest in seeing the research continue to develop. As a recent recruit to the U of A, I see it as a huge boost in confidence in the work that we do.