Cardiovascular disease remains the leading cause of death in the United States with up to 42% of sudden cardiac death in young adults caused by myocarditis. Adenovirus is now recognized as a leading etiological agent of viral myocarditis, yet our understanding of adenoviral infection in the heart is lacking due to viral host species specificity and historical difficulty in developing model systems of cardiac infection. In all forms of heart disease, subcellular remodeling of the cardiomyocyte occurs with disruptions in gap junction-mediated electrical coupling known to lead to fatal arrhythmias. The primary cardiac gap junction protein, connexin43 (Cx43), is now known to have internally translated isoforms that can modulate gap junction formation and cardiac health. Adenovirus hijacks host cell translational machinery to affect alternative translation initiation of viral and host mRNA, and such changes would rapidly affect the cardiomyocyte proteome and therefore electrical status of the heart. My proposed research will address gaps in the knowledge regarding mechanisms of arrhythmogenesis during acute viral myocarditis and the contribution of alterations in translation initiation to this process.
Aim 1 : Investigate arrhythmogenic mechanisms in an acute adenoviral myocarditis mouse model. Administering MAdv3 using a retro-orbital injection in C57/B6 mice, MAdv3 DNA is found preferentially in cardiac tissue. A mouse model will be defined for acute adenoviral myocarditis and their susceptibility to arrhythmogenesis.
Aim 2 : Determine the role of altered translation initiation in adenoviral-mediated cell junction remodeling. Many cellular junctional genes, such as Connexin 43 (Cx43), undergo alternate translation initiation to function properly. This alternate translation initiation is impaired in disease. Adenovirus modulates the host's translational machinery to favor alternate translation mechanisms for viral protein synthesis by maintaining levels of host cell?s eIF2? activity. The proposed research will broaden the understanding of how adenovirus infects the heart and causes sudden cardiac death during acute infection. Successful completion of the work proposed will provide a new model for acute viral myocarditis and provide insight into mechanisms of arrhythmogenesis. This proposal is significant because it will elucidate how adenovirus infects the working heart in an adult mouse model, how the infected cell's' translational landscape can lead to arrhythmogenesis, and it will test the potential of restoring of that landscape after infection in protection against sudden cardiac death.
Adenoviral myocarditis is one of the leading causes of sudden cardiac death in young adults, and currently, there is a lack of animal models for this disease. This research proposes to develop a murine model of acute adenoviral myocarditis, while defining host cellular translation initiation changes induced by adenoviral infection and their contribution to arrhythmogenesis.
