Ongoing coxsackievirus myocarditis is associated with increased formation and activity of myocardial immunoproteasomes.
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.
Szalay
Gudrun
G
Department of Molecular Pathology, University Hospital Tübingen, Germany. gnszalay@med.uni-tuebingen.de
Meiners
Silke
S
Voigt
Antje
A
Lauber
Jörg
J
Spieth
Christian
C
Speer
Nora
N
Sauter
Martina
M
Kuckelkorn
Ulrike
U
Zell
Andreas
A
Klingel
Karin
K
Stangl
Karl
K
Kandolf
Reinhard
R
D000818:Animals; D017951:Antigen Presentation / Q000502:physiology; D003384:Coxsackievirus Infections / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D015180:Electrophoresis, Gel, Two-Dimensional; D029822:Enterovirus B, Human / Q000276:immunology*; D006321:Heart / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008815:Mice, Inbred Strains; D009097:Multienzyme Complexes / Q000378:metabolism; D009205:Myocarditis / Q000139:chemically induced / Q000209:etiology / Q000276:immunology* / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D009928:Organ Specificity; D010447:Peptide Hydrolases / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000502:physiology*
D009097:Multienzyme Complexes; D010447:Peptide Hydrolases; C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex