Coxsackievirus B3 (CVB3) is etiologic in acute inflammatory heart disease which can be fatal outright (especially in young children) or which can become a chronic condition which requires massive clinical intervention. The initiating event in the inflammation of acute and chronic enteroviral heart disease is triggered by the cardiovirulent virus. Thus, our long- term goal is to establish those genetic changes which determine the CVB3 cardio-virulent phenotype, and to determine how a cardiovirulent phenotype interacts with cells in the heart and with the immune system to induce the myocarditis. This proposal's experiments will provide primary data which will be used to test mechanisms to provide answers to these questions. The results of the proposed work will provide an in-depth understanding of the pathogenesis of CVB-induced acute inflammatory myocardial disease. Because the acute viral disease precedes chronic conditions which often develop, this work will provide critical and as yet unavailable information regarding how chronic disease may arise from an acute inflammatory response to virus infection. These data will eventually facilitate development of intervention and prevention methodologies. This work will provide fundamental data on a common and serious enterovirus infection in the US and the world,providing a paradigm for the study of human enteroviral inflammatory diseases. Toward these ends, we have developed and characterized infectious cDNA clones of cardiovirulent and noncardiovirulent CVB3 genomes, and have begun to map genetic determinants of the virulence phenotype. We are mapping antigenic murine T cell epitopes in the CVB3 polypeptide to determine their roles in the acute disease. We have initiated studies using normal and SCID mice to test mechanisms for the involvement of the CMI response in murine cardiac CVB3 infections.
The specific aims are: [1] To map and define the determinants of the naturally occurring CVB3 cardiovirulent and attenuated phenotypes, using infectious CVB3 cDNA genomes constructed from non-virulent and virulent CVB3 genomes. The universality of these results will be tested using cloned sequences from other CVB3 isolates in similar constructs; [2] To map and define CVB3 antigenic epitopes recognized by murine T cells, to relate them to results from aim 1 and to test their significance in murine disease; [3] Explore and test mechanisms by which induction of the murine cardiac inflammatory response by CVB3 occurs.
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