Grant: Project Grant

Myocarditis is an inflammatory disorder of the heart muscle that is often caused by infection by a virus. Viral myocarditis remains the most common cause of heart failure and sudden death in children and young adults worldwide. Despite great efforts, there is still no clinically-proven treatment for this disease. The innate immune system acts as the first line of defense against invading viruses. However, it is becoming clear that excessive and sustained activation of this system can be harmful, leading to chronic inflammation and injuries to the heart. More importantly, clinical trials using broad immune suppressive drugs failed to show patient benefit because these drugs target both beneficial and detrimental immune responses. Therefore, it is vital to identify the specific immune pathway responsible for the adverse inflammatory response and understand how the virus interferes with this specific pathway. Our recent findings suggest that the cGAS-STING innate pathway, a major sensor of tissue damage, may play a key role in virus-associated heart inflammation and failure. The objective of this project is to understand how cGAS-STING signaling drives virus-induced myocarditis as a step towards developing an effective treatment for this disease. We will use heart and immune cells, genetically-engineered mouse models, and human myocarditis tissues to explore the significance of the cGAS-STING pathway in virus-induced inflammation and how it causes damage to the heart. We will also evaluate whether cGAS and STING inhibitors are effective in treating viral myocarditis in these experimental models. The research proposed in the current project will provide new information and advance our understanding regarding the mechanisms involved in the progression of viral myocarditis. Results from this work have tremendous potential to lead to new effective treatments for myocarditis.