Abstract 15528: Immunoproteasome Activation During Mouse Adenovirus Type 1 Myocarditis
The immunoproteasome (IP) is essential for generation of peptides that are presented by MHC class I molecules to CD8 T cells. IP activity is also critical for IκB degradation, facilitating NF κB-mediated activation of inflammatory responses. As such, the IP is likely to contribute to pathology in viral myocarditis. Adenoviruses (Ad) are common causes of viral myocarditis, but their strict species specificity precludes detailed studies of human Ad myocarditis. We have established mouse adenovirus type 1 (MAV-1) as a novel model to study Ad pathogenesis. We used MAV-1 to test the hypothesis that IP activation contributes to Ad-induced myocarditis. Neonatal C57BL/6 mice were infected intranasally with MAV-1 or mock infected with conditioned media. Routine staining was used to assess cardiac inflammation and myocyte damage. Real-time PCR was used to quantify DNA viral loads and mRNA levels of IFN-γ, a key inducer of IP activity, and IP subunits β5i, and PA28α. Western blot was used to quantify protein levels of IP subunits β5, β5i, PA28Sα, and PA28Sβ. Active β5 and β5i subunits were quantified using PROCISE assay. Peak IFN-γ upregulation and peak viral loads were detected at 10 days post infection (dpi). Cellular inflammation and myocyte necrosis were most pronounced between 10 and 14 dpi. PA28α and β5i mRNA levels were upregulated in infected hearts coincident with peak viral replication and IFN-γ expression. Similarly, there were substantial increases in β5i, PA28α, and PA28β protein and a striking decrease of β5 protein in infected hearts at 11 dpi (Table). We detected a corresponding increase in β5i active subunits and decrease in β5 active subunits, with an overall increase in the β5i:β5 ratio at 11 dpi (Table). MAV-1 infection causes myocarditis characterized by cellular inflammation, IFN-γ upregulation, and IP activation. Inhibition of IP activity may provide a novel approach to decrease cardiac damage induced by Ad or other pathogens.
- © 2013 by American Heart Association, Inc.