Project 457543

The heart fails when it cannot pump sufficiently to meet the needs of the body. In some patients who live with this condition, virus has been detected in the heart. While some patients can clear the virus and recover heart function, others progress to more severe disease. The reasons why a subset of patients develop chronic disease is still unclear, and it is important to study the factors that govern this transition as cardiovascular diseases are the leading cause of mortality worldwide. Many immune cells live within the heart, and macrophages are the most abundant. Macrophages were traditionally thought to be one homogenous cell type. Our recent work showed that some macrophages are present in the heart even before birth and persist into adulthood (embryonic macrophages). Another subset of macrophages is continuously replaced by new cells from the adult bone marrow. In the setting of viral infection of the heart, embryonic macrophages are lost, and there is a massive influx of new macrophages. These new macrophages are the dominant cell type that enters the heart during viral infection (termed myocarditis), but we still do not understand their function in this setting. While some studies showed that removing all macrophages following viral infection of the heart increases mortality of mice, others have shown that giving mice macrophages helps to clear the virus. Our work aims to resolve conflicting findings by investigating macrophages that enter the heart in particular stages of viral myocarditis. We will block the entry of macrophages during specific timepoints with a goal of understanding which subtypes of macrophages protect the heart versus which are damaging and promote injury. Genetic tools that can target specific macrophage subpopulations at precise timepoints are novel and have never been investigated in viral myocarditis. This work is critical for patients who develop severe heart disease without any effective treatments available.