Differential interferon responses enhance viral epitope generation by myocardial immunoproteasomes in murine enterovirus myocarditis.
Murine models of coxsackievirus B3 (CVB3)-induced myocarditis mimic the divergent human disease course of cardiotropic viral infection, with host-specific outcomes ranging from complete recovery in resistant mice to chronic disease in susceptible hosts. To identify susceptibility factors that modulate the course of viral myocarditis, we show that type-I interferon (IFN) responses are considerably impaired in acute CVB3-induced myocarditis in susceptible mice, which have been linked to immunoproteasome (IP) formation. Here we report that in concurrence with distinctive type-I IFN kinetics, myocardial IP formation peaked early after infection in resistant mice and was postponed with maximum IP expression concomitant to massive inflammation and predominant type-II IFN responses in susceptible mice. IP activity is linked to a strong enhancement of antigenic viral peptide presentation. To investigate the impact of myocardial IPs in CVB3-induced myocarditis, we identified two novel CVB3 T cell epitopes, virus capsid protein 2 [285-293] and polymerase 3D [2170-2177]. Analysis of myocardial IPs in CVB3-induced myocarditis revealed that myocardial IP expression resulted in efficient epitope generation. As opposed to the susceptible host, myocardial IP expression at early stages of disease corresponded to enhanced CVB3 epitope generation in the hearts of resistant mice. We propose that this process may precondition the infected heart for adaptive immune responses. In conclusion, type-I IFN-induced myocardial IP activity at early stages coincides with less severe disease manifestation in CVB3-induced myocarditis.
Jäkel
Sandra
S
Charité-Universitätsmedizin Berlin, Institut für Biochemie CC2, Monbijoustrasse 2, D-10117 Berlin, Germany.
Kuckelkorn
Ulrike
U
Szalay
Gudrun
G
Plötz
Michael
M
Textoris-Taube
Kathrin
K
Opitz
Elisa
E
Klingel
Karin
K
Stevanovic
Stefan
S
Kandolf
Reinhard
R
Kotsch
Katja
K
Stangl
Karl
K
Kloetzel
Peter M
PM
Voigt
Antje
A
D000818:Animals; D004195:Disease Models, Animal; D004770:Enterovirus / Q000276:immunology*; D004769:Enterovirus Infections / Q000150:complications / Q000276:immunology* / Q000473:pathology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006801:Humans; D007370:Interferon Type I / Q000276:immunology* / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009205:Myocarditis / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000276:immunology*
D018984:Epitopes, T-Lymphocyte; D007370:Interferon Type I; D046988:Proteasome Endopeptidase Complex