PKR, Myocarditis and the Cardiac Response to Reovirus Infection
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Date
2004-06-20
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Abstract
Viral myocarditis is an important human disease associated with many viruses. Mechanistically, cardiac damage associated with viral myocarditis can be immune mediated and/or the result of direct cytopathic effect. Reovirus induced myocarditis is not immune mediated, and thus, provides an excellent model for the study of direct cytopathic effect in the heart. Previous work has demonstrated that reovirus myocarditic potential reflects induction and/or sensitivity to interferon (IFN). Specifically, nonmyocarditic reoviruses induce greater IFN-β and/or are more sensitive to the antiviral effects IFN than are myocarditic reoviruses. Importantly, IFN mediates its antiviral effects through the induction of interferon-stimulated genes (ISGs); ISGs function as the antiviral effector proteins that block replication in the host cell.
The work presented in this dissertation further defines the cardiac response to reovirus infection. In chapter 2, we examined the double-stranded activated protein kinase PKR: the role of PKR in cardiac IFN induction and protection against reovirus-induced myocarditis. We demonstrate that PKR is critical to the robust induction of IFN-β in primary cardiac myocyte cultures (PCMCs). Additionally, we show that nonmyocarditic reoviruses become myocarditic in PKR-null mice, even though reovirus growth in PKR-null hearts is similar to that in wild type mouse hearts. Finally, we demonstrate that relative to wild type mice, reoviruses induce significantly greater morbidity in PKR-null mice.
In the following chapter, we compare the IFN response in PCMCs: a non-replenished, critical cell type, to that in primary cardiac fibroblast cultures (PCFCs): a readily replenished cardiac cell type. By quantitative real-time PCR, we find that PCMCs express IFN-β and the ISGs IRF-7 and 561 constitutively at higher levels than PCFCs. We also identify constitutive IFN as a primary means of constitutive ISG expression. Additionally, we demonstrate that PCFCs, more so than PCMCs are more dependent on IFN-mediated protection against reovirus infection.
The regulation of IFN-β expression is achieved primarily through the actions of Interferon Regulatory Factors (IRFs). In Appendix 1, we show contributions to a publication demonstrating that IRF-1 is dispensable for IFN-β induction in PCMCs, and yet critical for defense against reovirus-induced myocarditis in the mouse. Finally, a summary of this work is provided.
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Keywords
reovirus, myocarditis, PKR, interferon
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Degree
PhD
Discipline
Microbiology
