Enteroviruses are common human pathogens and, in some cases, are suspected of inducing myocarditis. The short term goal of the proposed research is to understand the contribution the cell mediated immune (CM1) response makes to the pathogenic mechanisms of enterovirus-induced myocarditis. The long range goals of this study are to identify precisely the viral epitopes which stimulate the T cell response and to determine which T cells, both functionally and by recognition pattern, are crucial for the induction of myocarditis. The current murine model of enterovirus-induced myocarditis involves infecting an enterovirus-seronegative mouse with an enterovirus, commonly coxsackievirus B3 (CVB3) to induce myocarditis have previously been exposed to one or more enteroviruses. Therefore, to mimic the condition in human disease, this study will examine a secondary model of enterovirus-induced myocarditis. Mice will receive an inoculation of CVB2 (amyocarditic) as a primary infection, followed twenty-eight days later with an inoculation of CVB3 (myocarditic) as a secondary infection. This combination of infections has been shown previously to increase markedly the pathology of myocarditis. To understand the mechanism(s) involved in the exacerbation of disease, this study proposes to examine, both in vitro, and in vivo components of the CM1 response. Specific mRNA for interleukin 2, gamma interferon, tumor necrosis factor-beta (lymphotoxin) and interleukin 2 receptor will be quantified from the hearts of both infected and reinfected mice using the highly sensitive polymerase chain reaction. In addition, clonal populations of T cells will be isolated from both enterovirus-infected and reinfected mice. The T cell clones will be used to identify the viral epitope recognized and to compare and contrast any differences in T cell stimulation between a primary and secondary response. Target cells for the clones will include MHC-matched fibroblasts infected with an vaccinia virus expressing a CVB3 protein or truncated protein of interest. Lastly, in an effort to determine the in vivo importance of the specific T cell subsets, isolated T cell clonal populations will be adoptively transferred to both normal and scid mice. These experiments will provide basic as well as novel information on the CM1 responses following enterovirus infection and reinfection, as well as providing information on viral T cell epitopes with the expectation that vaccines and more specific therapeutics can be developed.
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