20-40% of patients diagnosed with myocarditis or idiopathic dilated cardiomyopathy have been shown to have enteroviral RNA in their heart muscle, most likely resulting from infection with a coxsackievirus of the B (CVB) group. Studies of the murine model for myocarditis has also indicated that infection with cardiovirulent CVB3 results in persistence of viral RNA beyond the time at which infectious virus can be isolated. An investigation into the form of this persisting genomic RNA demonstrated that the enteroviral RNA has deletions of the extreme 5' end of the genome, a form which may have a more limited extent of replication than the wild type. This persisting virus can replicate in cell culture and can be passed but does not generate the classic cytopathic effect seen in cell culture of the wild type virus. This virus population displays interference with the replication of wild type CVBs. The hypothesis of this proposal is that deleted coxsackieviruses are generated in infection of the heart that limit replication and translation of this virus and interfere with remaining wild type virus so that virus persists. This persisting viral infection contributes to chronic inflammation and cardiomyopathy in later stage enterovirus-related inflammatory heart disease.
The specific aims of this proposal are to analyze the replication in cell culture of five deleted genomes that we have detected, and their ability to interfere with replication of wild type CVBs and to assay for similar deleted genomes in enterovirus-positive human heart biopsies and in murine heart tissue from mice infected with different CVB serotypes. The careful analysis of how these defective genomes replicate is likely to lead to an antiviral treatment which may provide means of halting the progression to cardiomyopathy and preventing the necessity for heart transplantation in perhaps a quarter of candidates for this radical treatment.
| Uchimura, Kenji; Morimoto-Tomita, Megumi; Bistrup, Annette et al. (2006) HSulf-2, an extracellular endoglucosamine-6-sulfatase, selectively mobilizes heparin-bound growth factors and chemokines: effects on VEGF, FGF-1, and SDF-1. BMC Biochem 7:2 |
| Kim, K-S; Tracy, S; Tapprich, W et al. (2005) 5'-Terminal deletions occur in coxsackievirus B3 during replication in murine hearts and cardiac myocyte cultures and correlate with encapsidation of negative-strand viral RNA. J Virol 79:7024-41 |
