Anna Rahnefeld1, Karin Klingel1, Anett Schuermann1, Nicola L Diny1, Nadine Althof1, Anika Lindner1, Philipp Bleienheuft1, Konstantinos Savvatis1, Dorota Respondek1, Elisa Opitz1, Lars Ketscher1, Martina Sauter1, Ulrike Seifert1, Carsten Tschöpe1, Wolfgang Poller1, Klaus-Peter Knobeloch1, Antje Voigt2. 1. From the Institut für Biochemie, Charité Universitätsmedizin Berlin, Berlin, Germany (A.R., A.S., N.A., A.L., P.B., D.R., E.O., A.V.); Molekulare Pathologie, Universitätsklinikum Tuebingen, Tuebingen, Germany (K.K., M.S.); Departments of Pathology and of Molecular Microbiology and Immunology and the Johns Hopkins Center for Autoimmune Disease Research, Johns Hopkins University, Baltimore, MD (N.L.D.); Medizinische Klinik für Kardiologie, Campus Benjamin Franklin, Charité Universitätsmedizin Berlin, Berlin, Germany (K.S., C.T., W.P.); Institut für Neuropathologie, Universitätsklinikum Freiburg, Freiburg, Germany (L.K., K.-P.K.); Institut für Molekulare und Klinische Immunologie, Otto-von-Guericke-Universität Magdeburg, Magdeburg, Germany (U.S.); and DZHK (German Centre for Cardiovascular Research), partner site Berlin, Germany (C.T., A.V.). 2. From the Institut für Biochemie, Charité Universitätsmedizin Berlin, Berlin, Germany (A.R., A.S., N.A., A.L., P.B., D.R., E.O., A.V.); Molekulare Pathologie, Universitätsklinikum Tuebingen, Tuebingen, Germany (K.K., M.S.); Departments of Pathology and of Molecular Microbiology and Immunology and the Johns Hopkins Center for Autoimmune Disease Research, Johns Hopkins University, Baltimore, MD (N.L.D.); Medizinische Klinik für Kardiologie, Campus Benjamin Franklin, Charité Universitätsmedizin Berlin, Berlin, Germany (K.S., C.T., W.P.); Institut für Neuropathologie, Universitätsklinikum Freiburg, Freiburg, Germany (L.K., K.-P.K.); Institut für Molekulare und Klinische Immunologie, Otto-von-Guericke-Universität Magdeburg, Magdeburg, Germany (U.S.); and DZHK (German Centre for Cardiovascular Research), partner site Berlin, Germany (C.T., A.V.). antje.voigt@charite.de.
Abstract
BACKGROUND: Common causative agents in the development of inflammatory cardiomyopathy include cardiotropic viruses such as coxsackievirus B3 (CVB3). Here, we investigated the role of the ubiquitin-like modifier interferon-stimulated gene of 15 kDa (ISG15) in the pathogenesis of viral cardiomyopathy. METHODS AND RESULTS: In CVB3-infected mice, the absence of protein modification with ISG15 was accompanied by a profound exacerbation of myocarditis and by a significant increase in mortality and heart failure. We found that ISG15 in cardiomyocytes contributed significantly to the suppression of viral replication. In the absence of an intact ISG15 system, virus titers were markedly elevated by postinfection day 8, and viral RNA persisted in ISG15(-/-) mice at postinfection day 28. Ablation of the ISG15 protein modification system in CVB3 infection predisposed mice to long-term disease with deposition of collagen fibers, all leading to inflammatory cardiomyopathy. We found that ISG15 acts as part of the intrinsic immunity in cardiomyocytes and detected no significant effects of ISG15 modification on the cellular immune response. ISG15 modification of CVB3 2A protease counterbalanced CVB3-induced cleavage of the host cell eukaryotic initiation factor of translation eIF4G in cardiomyocytes, thereby counterbalancing the shutoff of host cell translation in CVB3 infection. We demonstrate that ISG15 suppressed infectious virus yield in human cardiac myocytes and the induction of ISG15 in patients with viral cardiomyopathy. CONCLUSIONS: The ISG15 conjugation system represents a critical innate response mechanism in cardiomyocytes to fight the battle against invading pathogens, limiting inflammatory cardiomyopathy, heart failure, and death. Interference with the ISG15 system might be a novel therapeutic approach in viral cardiomyopathy.
BACKGROUND: Common causative agents in the development of inflammatory cardiomyopathy include cardiotropic viruses such as coxsackievirus B3 (CVB3). Here, we investigated the role of the ubiquitin-like modifier interferon-stimulated gene of 15 kDa (ISG15) in the pathogenesis of viral cardiomyopathy. METHODS AND RESULTS: In CVB3-infectedmice, the absence of protein modification with ISG15 was accompanied by a profound exacerbation of myocarditis and by a significant increase in mortality and heart failure. We found that ISG15 in cardiomyocytes contributed significantly to the suppression of viral replication. In the absence of an intact ISG15 system, virus titers were markedly elevated by postinfection day 8, and viral RNA persisted in ISG15(-/-) mice at postinfection day 28. Ablation of the ISG15 protein modification system in CVB3infection predisposed mice to long-term disease with deposition of collagen fibers, all leading to inflammatory cardiomyopathy. We found that ISG15 acts as part of the intrinsic immunity in cardiomyocytes and detected no significant effects of ISG15 modification on the cellular immune response. ISG15 modification of CVB3 2A protease counterbalanced CVB3-induced cleavage of the host cell eukaryotic initiation factor of translation eIF4G in cardiomyocytes, thereby counterbalancing the shutoff of host cell translation in CVB3infection. We demonstrate that ISG15 suppressed infectious virus yield in human cardiac myocytes and the induction of ISG15 in patients with viral cardiomyopathy. CONCLUSIONS: The ISG15 conjugation system represents a critical innate response mechanism in cardiomyocytes to fight the battle against invading pathogens, limiting inflammatory cardiomyopathy, heart failure, and death. Interference with the ISG15 system might be a novel therapeutic approach in viral cardiomyopathy.
Authors: Carolina Villarroya-Beltri; Francesc Baixauli; María Mittelbrunn; Irene Fernández-Delgado; Daniel Torralba; Olga Moreno-Gonzalo; Sara Baldanta; Carlos Enrich; Susana Guerra; Francisco Sánchez-Madrid Journal: Nat Commun Date: 2016-11-24 Impact factor: 14.919