The long-term goal of the proposed research is to correlate enteroviral presence in the heart, and perhaps other organs, with causation of acute myocarditis which progresses to chronic myocardial diseases such as dilated cardiomyopathies. The two specific aims of the work are (1) to examine the role of the inducing coxsackievirus B3 and murine genetic backgrounds through in situ hybridization detection of viral RNA in many murine tissues during disease progression following viral innoculation; (2) to sensitively probe human heart tissue and peripheral blood mononuclear cells of clinically well- characterized myocarditis patients and myocardium of explanted dilated hearts for the presence of enteroviral genomes and to develop a rapid, sensitive assay for enteroviral RNA using enzymatic amplication of nucleotide sequences and novel enhanced rate hybridization kinetics capable of detecting in the range of 10-100 enteroviral RNa molecules in biopsy within hours. The mouse model will be employed to determine what effects the virulence of the virus and the host genetic background have on viral persistence, disease progression, and presence of virus in the chronic phase of the disease and to draw inferences to the presumed homologous human situation. These experiments will provide essential data to evaluate whether enteroviruses remain in tissues other than heart following acute infection, perhaps acting as seeds to promote the inflammatory processes which have been demonstrated as deleterious to the heart in chronic disease. Screening of human hearts for enteroviral RNA, by in situ hybridization and later using a more sensitive approach developed in the course of this work, will determine whether enteroviral presence and presence of pathologic changes in the affected human organ can be correlated. Cumulatively, these experiments will determine whether there is justification to pursue prophylactic measures against specific enteroviruses as causes of human myocarditis and cardiomyopathies.
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