Abstract
Severe heart pathology upon virus infection is closely associated with the immunological equipment of the host. Since there is no specific treatment available, current research focuses on identifying new drug targets to positively modulate predisposing immune factors. Utilizing a murine model with high susceptibility to coxsackievirus B3‐induced myocarditis, this study describes ONX 0914—an immunoproteasome‐specific inhibitor—as highly protective during severe heart disease. Represented by reduced heart infiltration of monocytes/macrophages and diminished organ damage, ONX 0914 treatment reversed fulminant pathology. Virus‐induced immune response features like overwhelming pro‐inflammatory cytokine and chemokine production as well as a progressive loss of lymphocytes all being reminiscent of a sepsis‐like disease course were prevented by ONX 0914. Although the viral burden was only minimally affected in highly susceptible mice, resulting maintenance of immune homeostasis improved the cardiac output, and saved animals from severe illness as well as high mortality. Altogether, this could make ONX 0914 a potent drug for the treatment of severe virus‐mediated inflammation of the heart and might rank immunoproteasome inhibitors among drugs for preventing pathogen‐induced immunopathology.
Highlights
Severe heart pathology upon virus infection is closely associated with the immunological equipment of the host
Following up studies on previous work resolving proteasome biology in C57BL/6 mice with hereditary low susceptibility to virus-induced myocarditis (Jakel et al, 2009; Opitz et al, 2011; Rahnefeld et al, 2011; Ebstein et al, 2013), this mouse strain was treated with ONX 0914 and infected with a cardiotropic coxsackievirus B3 (CVB3) variant
In order to investigate whether the development of an adequate immune memory status is established unhindered as well, on day 28 after the initial virus infection, B6 mice were challenged a second time with CVB3
Summary
Severe heart pathology upon virus infection is closely associated with the immunological equipment of the host. Utilizing a murine model with high susceptibility to coxsackievirus B3-induced myocarditis, this study describes ONX 0914—an immunoproteasome-specific inhibitor—as highly protective during severe heart disease. The viral burden was only minimally affected in highly susceptible mice, resulting maintenance of immune homeostasis improved the cardiac output, and saved animals from severe illness as well as high mortality. This could make ONX 0914 a potent drug for the treatment of severe virus-mediated inflammation of the heart and might rank immunoproteasome inhibitors among drugs for preventing pathogen-induced immunopathology
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