Elucidating the Cardioprotective Role of Fetal-derived CD8+ T Cells During Viral-induced Myocarditis - Project Summary / Abstract In light of the recent pandemic of SARS-COV-2, clinical observations of myocarditis have become a topic of national and scientific concern, particularly among pediatrics. Many viral infections can lead to myocarditis where immune cells infiltrate the heart, such as cytomegalovirus (CMV). CMV seropositivity has been associated with worse cardiovascular disease later in life, however, the mechanism of how this occurs is unknown. The long- term goal of the applicant is to better understand the role the immune response plays in regulating homeostasis in the heart during development. The objective of this proposal is to establish how T cells made early in life that are recruited into the heart during myocarditis regulate the long-term consequences on cardiovascular disease. We know that fetal and adult derived CD8+ T cells are different in their developmental origin and functional capacity. This proposal will build from my previous work showing that based on timing of CMV infection, either fetal or adult CD8+ T cells are recruited to peripheral tissues and form tissue resident memory (TRM). This proposal will test the hypothesis that early-life CMV infection leads to a skewing of fetal-derived CD8+ T cells that form TRMs that results in increased tissue remodeling phenotype that has a functional impact on the development of cardiovascular disease later in life. In Aim1, I will phenotypically and functionally characterize fetal or adult derived TRMs and their physiological impact on cardiovascular disease progression. Aim 2 will investigate the unique molecular signatures of fetal or adult derived TRMs in the heart using single cell RNA- sequencing. Aim 3 will use spatial transcriptomics to analyze the three-dimensional space that fetal- versus adult-derived TRMs occupy in the heart. These findings will help provide fundamental knowledge to the field about the interplay of the immune response in the heart and address whether CMV seropositivity drives cardiovascular disease. The applicant will be combining their unique pre-doctoral training in cardiovascular disease, signal transduction and innate immune response with postdoctoral training in adaptive immune response, developmental immunology, and virology, making them uniquely qualified to answer these novel and clinically relevant questions. This K22 will be an invaluable asset to the applicant to formation of their own future NIH-funded research on the complex interplay between the immune response and cardiovascular disease.
