Determinants of host susceptibility to coxsackieviral myocarditis

grantor: University of TorontoViral myocarditis is an important cause of heart failure and dilated cardiomyopathy. Group B coxsackieviruses (CVBs) are commonly identified as the infectious agent responsible for acute myocarditis. This thesis examined the role of the T cell, the coxsackie-adenovirus receptor (CAR), and downstream signal transduction pathways in host susceptibility to CVB3 myocarditis. The first study, using gene-targeted T cell knockout mice, demonstrated that both CD4+ and CD8+ T cells contribute to the pathogenesis of myocarditis. The severity of myocardial damage and associated mortality depended upon the predominant T cell subset available to respond to CVB3 infection. Distinct cytokine patterns were found to be one mechanism by which CD4 + and CD8+ T cell subsets influence the pathogenesis of the disease. In the second study, it was hypothesized that the extracellular signal-regulated kinases (ERKs), which are stimulated following T cell receptor (TCR) engagement and Lck activation, influence host susceptibility to CVB3 infection and disease. In Jurkat T cells the ERK1/2 cascade is rapidly activated in an Lck-dependent manner at the time of initial virus-host cell interaction. Moreover, inhibition of the ERK1/2 cascade attenuates CVB3 replication in both T cells and cardiomyocytes. Myocarditis-susceptible A/J mice infected with CVB3 showed exuberant activation of the ERK1/2 signalling pathway. In contrast, activation was weaker and transient in C57BL/6 mice, which are resistant to myocarditis. The ERK1/2 signalling cascade is triggered by CVB3 infection and correlated with severity of viral myocarditis. The third study explored the viral receptor as a determinant of myocarditis susceptibility. CAR expression was highest in the hearts of myocarditis-susceptible A/J mice, which were found to have high cardiac CVB3 titres following infection. A truncated CAR isoform was identified, which bound virus, but did not mediate productive infection. Tissue abundance of CAR and differential expression of receptor isoforms may determine myocarditis susceptibility. Thus, the initial virus-receptor interaction, the T cell response, cytokine activation, and downstream signal transduction pathways in both the T lymphocyte and the heart, appear to affect host cell function and viral replication, influencing host susceptibility to myocarditis.Ph.D