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EMBO Mol Med. 2018 Feb;10(2):200-218. doi: 10.15252/emmm.201708089.

The immunoproteasome-specific inhibitor ONX 0914 reverses susceptibility to acute viral myocarditis.

Author information

1
Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Institute of Biochemistry, Berlin, Germany.
2
Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK), partner side Berlin, Berlin, Germany.
3
Max-Delbrueck-Center for Molecular Medicine Berlin, Berlin, Germany.
4
Medizinische Klinik für Innere Medizin III: Kardiologie, Angiologie und Pneumologie, Universitätsklinikum Heidelberg, Heidelberg, Germany.
5
Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK), partner side Heidelberg, Heidelberg, Germany.
6
Cardiopathology, Institute for Pathology and Neuropathology, University Hospital Tuebingen, Tuebingen, Germany.
7
Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Institute of Biochemistry, Berlin, Germany antje.beling@charite.de.

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.

KEYWORDS:

immunology and inflammation; infectious diseases; myocarditis; proteasome; virus

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