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(American Journal of Pathology. 2006;168:1542-1552.)
© 2006 American Society for Investigative Pathology

Ongoing Coxsackievirus Myocarditis Is Associated with Increased Formation and Activity of Myocardial Immunoproteasomes

Gudrun Szalay*, Silke Meiners{dagger}, Antje Voigt{dagger}{ddagger}, Jörg Lauber§, Christian Spieth, Nora Speer, Martina Sauter*, Ulrike Kuckelkorn{ddagger}, Andreas Zell, Karin Klingel*, Karl Stangl{dagger} and Reinhard Kandolf*

From the Department of Molecular Pathology, University Hospital Tübingen,* Tübingen; Clinic for Cardiology, Angiology, and Pneumology,{dagger} and Institute of Biochemistry,{ddagger} Charité-Universitätsmedizin, Berlin; the German Research Center for Biotechnology,§ Braunschweig; and the Center for Bioinformatics Tübingen, Eberhard-Karls-University, Tübingen, Germany

A growing body of evidence indicates that viral infections of the heart contribute to ongoing myocarditis and dilated cardiomyopathy. Murine models of coxsackievirus B3 (CVB3)-induced myocarditis mimic the human disease and allow identification of susceptibility factors that modulate the course of viral myocarditis. Susceptible mouse strains develop chronic myocarditis on the basis of restricted viral replication, whereas resistant strains recover after successful virus elimination. In comparative whole-genome microarray analyses of infected hearts, several genes involved in the processing and presentation of viral epitopes were found to be uniformly up-regulated in acutely CVB3-infected susceptible mice compared with resistant animals. In particular, expression of the catalytic subunits LMP2, LMP7, and MECL-1, immunoproteasome proteins important in the generation of major histocom-patibility complex (MHC) class I-restricted peptides, was clearly enhanced in the susceptible host. Increased expression resulted in enhanced formation of immunoproteasomes and altered proteolytic activities of proteasomes in the heart. This was accompanied by a concerted up-regulation of the antigen-presenting machinery in susceptible mice. Thus, we propose that increased formation of immunoproteasomes in susceptible mice affects the generation of antigenic peptides and the subsequent T-cell-mediated immune responses.






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Copyright © 2006 by the American Society for Investigative Pathology.