From the Department of Medicine, University of California, San Diego,
School of Medicine (R.W., K.U.K.); the Institut für Virologie, Friedrich
Schiller Universität, Jena, Germany (A.H., R.Z.); and the Institute for
Pathology, Department of Molecular Pathology, University of Tübingen,
Germany (R.K.). R.W. is now at the Cardiology Division, German Heart Center,
Klinik an der Technichsen Universitaet, Munich, Germany.
Correspondence to Kirk U. Knowlton, MD, Department of Medicine, 0613c, University of California, San Diego, 9500 Gilman Dr, San Diego, CA 92093-0613. E-mail kknowlton{at}ucsd.edu
Background—Enteroviral ribonucleic
acids have been identified in heart muscle of a subset of patients with
myocarditis and dilated cardiomyopathy as well as
in a mouse model of persistent coxsackievirus B3 (CVB3) infection,
suggesting that persistent viral infection along with activation of an
immune response may contribute to the pathogenesis of ongoing cardiac
disease and dilated cardiomyopathy in certain
patients. It is still not known whether persistence of the viral genome
contributes to the pathogenesis of dilated cardiomyopathy.
Methods and Results—To determine whether low-level enteroviral
gene expression similar to that observed with viral persistence can
induce myocytopathic effects without formation of infectious virus
progeny, the full-length infectious cDNA copy of CVB3 was mutated at
the VP0 maturation cleavage site. This prevented formation of
infectious virus progeny. In myocytes transfected with this mutated
cDNA copy of the viral genome, both positive- and negative-strand viral
RNAs were detected, demonstrating that there was replication of the
viral genome by the RNA-dependent RNA polymerase. The level of viral
protein expression was found to be below limits of detection by
conventional methods of protein detection, thus resembling restricted
virus replication. Nonetheless, the CVB3 mutant was found to induce a
cytopathic effect in transfected myocytes, which was demonstrated by
inhibition of cotransfected MLC-2v luciferase reporter activity and an
increase in release of lactate dehydrogenase from transfected
cells.
Conclusions—This study demonstrates that restricted replication
of enteroviral genomes in myocytes in a pattern similar to that
observed in hearts with persistent viral infection can induce
myocytopathic effects without generation of infectious virus progeny.
© 1998 American Heart Association, Inc.
Basic Science Reports
Low-Level Expression of a Mutant Coxsackieviral cDNA Induces a Myocytopathic Effect in Culture
An Approach to the Study of Enteroviral Persistence in Cardiac Myocytes
Key Words: viruses • myocarditis • heart failure
This article has been cited by other articles:
 |
|
 |
|
  R. Feuer, C. M. Ruller, N. An, J. M. Tabor-Godwin, R. E. Rhoades, S. Maciejewski, R. R. Pagarigan, C. T. Cornell, S. J. Crocker, W. B. Kiosses, et al. Viral Persistence and Chronic Immunopathology in the Adult Central Nervous System following Coxsackievirus Infection during the Neonatal Period J. Virol., September 15, 2009; 83(18): 9356 - 9369. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Xiong, T. Yajima, B.-K. Lim, A. Stenbit, A. Dublin, N. D. Dalton, D. Summers-Torres, J. D. Molkentin, H. Duplain, R. Wessely, et al. Inducible Cardiac-Restricted Expression of Enteroviral Protease 2A Is Sufficient to Induce Dilated Cardiomyopathy Circulation, January 2, 2007; 115(1): 94 - 102. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Rassmann, A. Henke, M. Zobawa, M. Carlsohn, H.-P. Saluz, S. Grabley, F. Lottspeich, and T. Munder Proteome alterations in human host cells infected with coxsackievirus B3 J. Gen. Virol., September 1, 2006; 87(9): 2631 - 2638. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. S. Fujinami, M. G. von Herrath, U. Christen, and J. L. Whitton Molecular Mimicry, Bystander Activation, or Viral Persistence: Infections and Autoimmune Disease Clin. Microbiol. Rev., January 1, 2006; 19(1): 80 - 94. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K.-S. Kim, S. Tracy, W. Tapprich, J. Bailey, C.-K. Lee, K. Kim, W. H. Barry, and N. M. Chapman 5'-Terminal Deletions Occur in Coxsackievirus B3 during Replication in Murine Hearts and Cardiac Myocyte Cultures and Correlate with Encapsidation of Negative-Strand Viral RNA J. Virol., June 1, 2005; 79(11): 7024 - 7041. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Merl, C. Michaelis, B. Jaschke, M. Vorpahl, S. Seidl, and R. Wessely Targeting 2A Protease by RNA Interference Attenuates Coxsackieviral Cytopathogenicity and Promotes Survival in Highly Susceptible Mice Circulation, April 5, 2005; 111(13): 1583 - 1592. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Kuhl, M. Pauschinger, P. L. Schwimmbeck, B. Seeberg, C. Lober, M. Noutsias, W. Poller, and H.-P. Schultheiss Interferon-{beta} Treatment Eliminates Cardiotropic Viruses and Improves Left Ventricular Function in Patients With Myocardial Persistence of Viral Genomes and Left Ventricular Dysfunction Circulation, June 10, 2003; 107(22): 2793 - 2798. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Wessely, L. Hengst, B. Jaschke, F. Wegener, T. Richter, R. Lupetti, M. Paschalidis, A. Schomig, R. Brandl, and F.-J. Neumann A central role of interferon regulatory factor-1 for the limitation of neointimal hyperplasia Hum. Mol. Genet., January 15, 2003; 12(2): 177 - 187. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Poller, H. Fechner, M. Noutsias, C. Tschoepe, M. Pauschinger, and H.-P. Schultheiss The molecular basis of cardiotropic viral infections Eur. Heart J. Suppl., December 1, 2002; 4(suppl_I): I18 - I30. [Abstract] [PDF]
|
|
|
|
|
|
S. A. Huber, D. Sartini, and M. Exley V{gamma}4+ T Cells Promote Autoimmune CD8+ Cytolytic T-Lymphocyte Activation in Coxsackievirus B3-Induced Myocarditis in Mice: Role for CD4+ Th1 Cells J. Virol., October 2, 2002; 76(21): 10785 - 10790. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. M. Zhang, B. Yanagawa, P. Cheung, H. Luo, J. Yuan, D. Chau, A. Wang, L. Bohunek, J. E. Wilson, B. M. McManus, et al. Nip21 Gene Expression Reduces Coxsackievirus B3 Replication by Promoting Apoptotic Cell Death via a Mitochondria-Dependent Pathway Circ. Res., June 28, 2002; 90(12): 1251 - 1258. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Feuer, I. Mena, R. Pagarigan, M. K. Slifka, and J. L. Whitton Cell Cycle Status Affects Coxsackievirus Replication, Persistence, and Reactivation In Vitro J. Virol., March 27, 2002; 76(9): 4430 - 4440. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Luo, B. Yanagawa, J. Zhang, Z. Luo, M. Zhang, M. Esfandiarei, C. Carthy, J. E. Wilson, D. Yang, and B. M. McManus Coxsackievirus B3 Replication Is Reduced by Inhibition of the Extracellular Signal-Regulated Kinase (ERK) Signaling Pathway J. Virol., March 7, 2002; 76(7): 3365 - 3373. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Peng, T. Sadusky, Y. Li, G. R. Coulton, H. Zhang, and L. C. Archard Altered expression of Bag-1 in Coxsackievirus B3 infected mouse heart Cardiovasc Res, April 1, 2001; 50(1): 46 - 55. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Wada, K. Saito, T. Kanda, I. Kobayashi, H. Fujii, S. Fujigaki, N. Maekawa, H. Takatsu, H. Fujiwara, K. Sekikawa, et al. Tumor Necrosis Factor-{{alpha}} (TNF-{{alpha}}) Plays a Protective Role in Acute Viral Myocarditis in Mice : A Study Using Mice Lacking TNF-{{alpha}} Circulation, February 6, 2001; 103(5): 743 - 749. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Wessely, K. Klingel, K. U. Knowlton, and R. Kandolf Cardioselective Infection With Coxsackievirus B3 Requires Intact Type I Interferon Signaling : Implications for Mortality and Early Viral Replication Circulation, February 6, 2001; 103(5): 756 - 761. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M T Kearney, J M Cotton, P J Richardson, and A M Shah Viral myocarditis and dilated cardiomyopathy: mechanisms, manifestations, and management Postgrad. Med. J., January 1, 2001; 77(903): 4 - 10. [Abstract] [Full Text]
|
|
|
|
 |
|
 S. Fujioka, Y. Kitaura, A. Ukimura, H. Deguchi, K. Kawamura, T. Isomura, H. Suma, and A. Shimizu Evaluation of viral infection in the myocardium of patients with idiopathic dilated cardiomyopathy J. Am. Coll. Cardiol., November 15, 2000; 36(6): 1920 - 1926. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Heim, S. Zeuke, S. Weiss, W. Ruschewski, and I. M. Grumbach Transient Induction of Cytokine Production in Human Myocardial Fibroblasts by Coxsackievirus B3 Circ. Res., April 14, 2000; 86(7): 753 - 759. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. E. Tam and R. P. Messner Molecular Mechanisms of Coxsackievirus Persistence in Chronic Inflammatory Myopathy: Viral RNA Persists through Formation of a Double-Stranded Complex without Associated Genomic Mutations or Evolution J. Virol., December 1, 1999; 73(12): 10113 - 10121. [Abstract] [Full Text]
|
|
|
|
|
|
K. U. Knowlton and C. Badorff The Immune System in Viral Myocarditis : Maintaining the Balance Circ. Res., September 17, 1999; 85(6): 559 - 561. [Full Text] [PDF]
|
|