National Institute of Allergy and Infectious Diseases 1F30AI188889-01A1

T lymphocyte bystander responses in male-biased myocarditis

This award funds research on the immune mechanisms behind male-biased myocarditis, focusing on IL-15-induced bystander T cell responses and the influence of androgens, using a mouse model to better understand and potentially improve treatment and vaccine development.

Description

Myocarditis, which is inflammation of the heart muscle mediated by immune cell infiltration and tissue damage, can lead to cardiac dysfunction or sudden death. The most common cause of myocarditis is viral infection, followed by other triggers including mRNA vaccination. Myocarditis, including after viral infection and vaccination, is more frequently seen in males, yet underlying mechanisms remain incompletely understood. A clearer understanding of male-biased myocarditis is essential for improving disease management and optimizing vaccine development. Previous work demonstrated that relative to healthy vaccinated controls, mRNA vaccine-associated myocarditis patients have elevations in circulating cytokines like IL-15, which activates T cells and innate-like bystander responses, coupled with increased peripheral activated cytotoxic T cells upregulating chemokine receptors, including CXCR3 and CCR5, implicated in heart tissue infiltration and site-specific bystander activation. Histopathological examination of patient heart biopsies confirmed predominant T cell infiltration. These immune responses have similarly been implicated in viral myocarditis, suggesting a potentially key role in male-biased heart inflammation. The study hypothesizes that IL-15-induced bystander cytotoxic T cell responses mediate male-biased heart inflammation in an androgen-enhanced manner. The project aims to define the role of IL-15-induced bystander T cells in male-biased heart inflammation using a developed mouse model and to test effects of androgen deprivation and supplementation.

View original record