Elucidating the innate and adaptive immune mechanism differences during viral myocarditis between pediatric and adult populations: role of sex, age and hormone status - PROJECT SUMMARY Myocarditis is a leading cause of sudden death in children and young adults but is understudied, especially in children. Viral myocarditis, inflammation of the heart muscle, has been found to involve both the innate and adaptive immune response in adult myocarditis models, but before this study, there were no mouse models for pediatric viral myocarditis; therefore, this is unstudied in the pediatric population. Our long-term goal is to evaluate the development and progression of myocarditis, dilated cardiomyopathy, and heart failure across the lifespan. Our overall objective of this application is to determine how the immune mechanisms differ between pediatric and adult mice and patients leading to and during myocarditis. Our central hypothesis is that younger pediatric mice and patients, before the onset of puberty, will develop a stronger innate and adaptive immune response, leading to severe disease during myocarditis. This hypothesis will be tested with the following two specific aims: 1) Identify the differences in immune biomarkers between pediatric and adult myocarditis patients by sex and age. 2) Determine how age and hormone status alter the immune response, leading to altered viral myocarditis severity in a translational mouse model by sex. Under the first aim, we will utilize 550 adult and pediatric patient blood samples/clinical data to investigate if patient age alters immune biomarkers predicting disease severity based on cardiac function and/or standard laboratory values in myocarditis patients by sex. For the second aim, we will first examine innate and adaptive immune mechanism differences between pediatric and adult mice in myocarditis utilizing female and male 3-week, 4-week, and 8-week-old mice. We will assess differences in the inflammasome, complement, and antibody response at 48, 5 days, and 10 days post-infection. Next, we will investigate the role of sex hormones in pediatric and adult mice to determine if age differences are due to estrogen and testosterone changes during puberty and aging. We will utilize gonadectomy at various ages to study the influence of hormones on innate and adaptive immune responses in male and female mice. Additionally, we will utilize aged male mice and a VCD-induced ovarian failure model in female mice to study the effect of menopause/andropause on myocarditis mechanisms. The research proposed in this application is innovative because it departs from the status quo and studies the differences between pediatric and adult mouse populations using the first pediatric viral myocarditis mouse model. The proposed research is significant because it is expected to identify how the age of patients/mice could influence the innate and adaptive immune response leading to myocarditis severity or progression. This will have a positive impact as it is expected to significantly impact the myocarditis field by providing a mechanistic understanding of how sex, age, and hormone status interplay in response to viral infection during acute myocarditis and will lead to targeted treatments in an individualized manner and provide a better understanding of pediatric disease.
