title: Ubiquitin-like protein ISG15 (interferon-stimulated gene of 15 kDa) in host defense against heart failure in a mouse model of virus-induced cardiomyopathy.
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.
  
  
  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.
authors.affiliation: 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.).
authors.forename: Anna
authors.initials: A
authors.lastname: Rahnefeld
authors.affiliation: 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.).
authors.forename: Karin
authors.initials: K
authors.lastname: Klingel
authors.affiliation: 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.).
authors.forename: Anett
authors.initials: A
authors.lastname: Schuermann
authors.affiliation: 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.).
authors.forename: Nicola L
authors.initials: NL
authors.lastname: Diny
authors.affiliation: 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.).
authors.forename: Nadine
authors.initials: N
authors.lastname: Althof
authors.affiliation: 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.).
authors.forename: Anika
authors.initials: A
authors.lastname: Lindner
authors.affiliation: 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.).
authors.forename: Philipp
authors.initials: P
authors.lastname: Bleienheuft
authors.affiliation: 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.).
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Savvatis
authors.affiliation: 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.).
authors.forename: Dorota
authors.initials: D
authors.lastname: Respondek
authors.affiliation: 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.).
authors.forename: Elisa
authors.initials: E
authors.lastname: Opitz
authors.affiliation: 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.).
authors.forename: Lars
authors.initials: L
authors.lastname: Ketscher
authors.affiliation: 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.).
authors.forename: Martina
authors.initials: M
authors.lastname: Sauter
authors.affiliation: 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.).
authors.forename: Ulrike
authors.initials: U
authors.lastname: Seifert
authors.affiliation: 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.).
authors.forename: Carsten
authors.initials: C
authors.lastname: Tschöpe
authors.affiliation: 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.).
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Poller
authors.affiliation: 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.).
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Knobeloch
authors.affiliation: 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.
authors.forename: Antje
authors.initials: A
authors.lastname: Voigt
mesh_terms: D000328:Adult; D000818:Animals; D001706:Biopsy; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000276:immunology / Q000821:virology*; D003384:Coxsackievirus Infections / Q000150:complications* / Q000235:genetics / Q000276:immunology; D003546:Cysteine Endopeptidases / Q000276:immunology; D016207:Cytokines / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D029822:Enterovirus B, Human / Q000276:immunology*; D005260:Female; D006333:Heart Failure / Q000235:genetics / Q000276:immunology / Q000821:virology*; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology / Q000821:virology; D008297:Male; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000502:physiology / Q000821:virology; D013601:T-Lymphocytes / Q000276:immunology / Q000821:virology; D014452:Ubiquitins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014764:Viral Proteins / Q000276:immunology; D014779:Virus Replication
chemical_list: D016207:Cytokines; C489550:G1p2 protein, mouse; D014452:Ubiquitins; D014764:Viral Proteins; D003546:Cysteine Endopeptidases; C057400:picornain 2A, Picornavirus
keywords: ISG15 protein, human; cardiomyopathy, dilated; immunology; infection; inflammation; interferon type I; models, animal; myocarditis; viruses