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Mechanisms and Prevention of Coxsackievirus B3-Induced Myocarditis
Myocarditis is an inflammatory disease of the myocardium. In humans, viruses are commonly suspected as causative agents, including coxsackievirus B3 (CVB3), a member of the Enterovirus genus of the Picornaviridae family. Individuals afflicted with myocarditis can chronically develop dilated cardiomyopathy (DCM), a condition characterized by cardiac remodeling that can lead to heart failure. Pathogenic mechanisms underpinning DCM, however, remain largely unknown. No vaccines are currently available to prevent infections by enteroviruses. To fill these gaps, we sought to dissect the cellular compositions of heart tissues and infiltrates in CVB3-induced myocarditis, and developed a vaccine candidate to prevent CVB infections. First, by performing single-cell RNA sequencing on heart cells from myocarditic mice, we identified M2 macrophages, T cells, and fibroblasts as the significant contributors to inflammation in post-infectious myocarditis. This analysis led us to identify unique sets of transcription factors in each cell population that could potentially be targeted for therapy. Second, we identified the immunogenic epitopes in the viral protein (VP)1 of CVB3 and used this information to create major-histocompatibility complex class II dextramers and tetramers, which allowed us to analyze antigen-specific T cell responses in CVB infections. Third, we successfully developed a novel live-attenuated vaccine virus (Mutant 10 or Mt 10), bearing the single amino acid substitution H790A in CVB3 VP1. Immunization with Mt 10 vaccine completely protected mice against CVB3-induced myocarditis and pancreatitis by inducing VP1-reactive virus-neutralizing antibodies and antigen-specific T cell responses. Finally, by establishing a CVB4 infection model in A/J mice, we demonstrated that the vaccine virus could also protect against CVB4 infection. The data suggest that the Mt 10 vaccine has the potential to prevent infections caused by multiple CVB serotypes.
Lasrado, Ninaad, "Mechanisms and Prevention of Coxsackievirus B3-Induced Myocarditis" (2022). ETD collection for University of Nebraska - Lincoln. AAI29252885.