Research Article Cardiac Fibroblasts Aggravate Viral Myocarditis: Cell Specific Coxsackievirus B3 Replication Diana Lindner, 1,2 Jia Li, 1 Konstantinos Savvatis, 3 Karin Klingel, 4 Stefan Blankenberg, 1,2 Carsten Tschöpe, 3,5 and Dirk Westermann 1,2 1 Clinic for General and Interventional Cardiology, University Heart Center Hamburg, Martinistraße 52, 20246 Hamburg, Germany 2 German Center for Cardiovascular Research (DZHK), Partner Sites, Hamburg/Kiel/L¨ ubeck, Germany 3 Department of Cardiology and Pneumology, Charit´ e-Universit¨ atsmedizin Berlin, Campus Benjamin Franklin (CBF), Berlin, Germany 4 Department of Molecular Pathology, Institute for Pathology, Eberhard Karls University of T¨ ubingen, T¨ ubingen, Germany 5 German Center for Cardiovascular Research (DZHK), Partner Sites, Berlin, Germany Correspondence should be addressed to Diana Lindner; d.lindner@uke.de and Dirk Westermann; dirk.westermann@web.de Received 30 April 2014; Revised 22 August 2014; Accepted 25 August 2014; Published 13 October 2014 Academic Editor: Teresa Zelante Copyright © 2014 Diana Lindner et al. his is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Myocarditis is an inlammatory disease caused by viral infection. Diferent subpopulations of leukocytes enter the cardiac tissue and lead to severe cardiac inlammation associated with myocyte loss and remodeling. Here, we study possible cell sources for viral replication using three compartments of the heart: ibroblasts, cardiomyocytes, and macrophages. We infected C57BL/6j mice with Coxsackievirus B3 (CVB3) and detected increased gene expression of anti-inlammatory and antiviral cytokines in the heart. Subsequently, we infected cardiac ibroblasts, cardiomyocytes, and macrophages with CVB3. Due to viral infection, the expression of TNF-, IL-6, MCP-1, and IFN- was signiicantly increased in cardiac ibroblasts compared to cardiomyocytes or macrophages. We found that in addition to cardiomyocytes cardiac ibroblasts were infected by CVB3 and displayed a higher virus replication (132-fold increase) compared to cardiomyocytes (14-fold increase) between 6 and 24 hours ater infection. At higher virus concentrations, macrophages are able to reduce the viral copy number. At low virus concentration a persistent virus infection was determined. herefore, we suggest that cardiac ibroblasts play an important role in the pathology of CVB3-induced myocarditis and are another important contributor of virus replication aggravating myocarditis. 1. Introduction Myocarditis is an inlammatory disease of the heart muscle oten resulting in cardiac dysfunction and death, especially in young patients [1, 2]. he gold standard for diagnosing myocarditis is based on histopathology from endomyocardial biopsies, in which clear inlammatory cellular iniltrates are present [1, 3–5]. One of the most common causes for acute myocarditis is a cardiac infection with viruses, especially with enteroviruses of the Coxsackievirus B family [1, 6, 7]. his virus-induced myocarditis remains still one major cause of dilated car- diomyopathy. Virus-mediated cell lysis leads to destruction of cardiac cells, especially cardiomyocytes. he destroyed cardiomyocytes are then replaced by ibrosis which inally may lead to dilated cardiomyopathy. CVB3-induced viral myocarditis is a well-established model to elucidate viral myocarditis in mice [8–14]. In this model, mice were infected intraperitoneally with CVB3 and within a few days a severe inlammation and virus replication can be observed in the cardiac tissue. In general, cells of the innate immune system identify and engulf pathogens, which are proteolytically processed and then presented as peptides that are presented as antigens to cells of the adaptive immune system [15, 16]. But it is known that those cells can also be infected by virus suggesting that they may transport virus particles into organs and infect resident cells [17]. Increased gene expression of pro- and anti-inlammatory as well as antiviral cytokines could be observed in infected cardiac tissue [11–13, 18, 19]. But those cytokines can be expressed due to the iniltration of inlammatory cells or due to activation of resident cardiac cells triggered by viral infection [18–20]. Hindawi Publishing Corporation Mediators of Inflammation Volume 2014, Article ID 519528, 14 pages http://dx.doi.org/10.1155/2014/519528