Immunoproteasome Inhibition Confers Protective Effects in a Murine Model of Adenovirus Myocarditis
Greiner, Kaitlyn E.
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Myocarditis is an inflammatory disorder that affects the myocardium, or the muscle tissue of the heart. Myocarditis is commonly caused by viral infection, and adenoviruses are frequently identified in patients with myocarditis. Because adenoviruses are host-specific, we used mouse adenovirus type 1 (MAV-1) to study adenovirus myocarditis in vivo. During viral myocarditis, the host immune response functions to limit viral replication, but the ensuing inflammation may also damage the infected heart. The immunoproteasome is an alternative form of the constitutive proteasome that is active during inflammation. Prior research has demonstrated the importance of immunoproteasomes in MHC class I presentation of viral epitopes, inflammatory signaling via the NF-kB pathway, and modulation of oxidative stress responses. We hypothesized that immunoproteasome activity both facilitates viral clearance and contributes to detrimental inflammation during adenovirus myocarditis. To test this hypothesis, we used ONX-0914, a selective inhibitor of the p5i immunoproteasome subunit, to characterize the role of immunoproteasomes in MAV-1 infection. We used RT-qPCR and qPCR to quantify expression of inflammatory markers and viral loads, respectively. Intranasal MAV-1 infection of neonatal mice induced cellular inflammation, upregulated expression of multiple pro-inflammatory cytokines, and decreased cardiac function at 10 days post infection (dpi). ONX-0914treatment of neonatal mice beginning at 6 dpi led to decreased expression of pro-inflammatory cytokines and decreased cellular inflammation at 9 dpi. Our work suggests that immunoproteasome activity contributes to cardiac damage during adenoviral infection, and it points towards immunoproteasome modulation as a potential therapy for adenovirus myocarditis.