The prostacyclin agonist iloprost aggravates fibrosis and enhances viral replication in enteroviral myocarditis by modulation of ERK signaling and increase of iNOS expression.

Enteroviruses, such as coxsackieviruses of group B (CVB), are able to induce a chronic inflammation of the myocardium, which may finally lead to the loss of functional tissue, remodeling processes and the development of fibrosis, thus affecting the proper contractile function of the heart. In other fibrotic diseases like scleroderma, the prostacyclin agonist iloprost was found to inhibit the extracellular signal-regulated kinase (ERK, p44/42 MAPK), a mitogen-activated protein kinase, and consecutively, the expression of the profibrotic cytokine connective tissue growth factor (CTGF), thereby preventing the development of fibrosis. As CTGF was found to mediate fibrosis in chronic CVB3 myocarditis as well, we evaluated whether the in vivo application of iloprost is capable to reduce the development of ERK/CTGF-mediated fibrosis in enteroviral myocarditis.

Generation of in silico predicted coxsackievirus B3-derived MHC class I epitopes by proteasomes.

Proteasomes are known to be the main suppliers of MHC class I (MHC-I) ligands. In an attempt to identify coxsackievirus B3 (CVB3)-MHC-I epitopes, a combined approach of in silico MHC-I/transporters associated with antigen processing (TAP)-binding and proteasomal cleavage prediction was applied. Accordingly, 13 potential epitopes originating from the structural and non-structural protein region of CVB3 were selected for further in vitro processing analysis by proteasomes.

Differential interferon responses enhance viral epitope generation by myocardial immunoproteasomes in murine enterovirus myocarditis.

Murine models of coxsackievirus B3 (CVB3)-induced myocarditis mimic the divergent human disease course of cardiotropic viral infection, with host-specific outcomes ranging from complete recovery in resistant mice to chronic disease in susceptible hosts. To identify susceptibility factors that modulate the course of viral myocarditis, we show that type-I interferon (IFN) responses are considerably impaired in acute CVB3-induced myocarditis in susceptible mice, which have been linked to immunoproteasome (IP) formation. Here we report that in concurrence with distinctive type-I IFN kinetics, myocardial IP formation peaked early after infection in resistant mice and was postponed with maximum IP expression concomitant to massive inflammation and predominant type-II IFN responses in susceptible mice.

Osteopontin: a fibrosis-related marker molecule in cardiac remodeling of enterovirus myocarditis in the susceptible host.

The characteristics of dilated cardiomyopathy (DCM) resulting from chronic viral myocarditis are remodeling processes of the extracellular matrix. Based on our findings of enhanced osteopontin (OPN) expression in inflamed human hearts, we further investigated in the murine model of acute and chronic coxsackievirus (CV)B3-myocarditis the role of OPN regarding its involvement in resolution of cardiac virus infection and fibrosis. In hearts of A.

Effective chemokine secretion by dendritic cells and expansion of cross-presenting CD4-/CD8+ dendritic cells define a protective phenotype in the mouse model of coxsackievirus myocarditis.

Enteroviruses such as coxsackievirus B3 (CVB3) are able to induce lethal acute and chronic myocarditis. In resistant C57BL/6 mice, CVB3 myocarditis is abrogated by T-cell-dependent mechanisms, whereas major histocompatibility complex (MHC)-matched permissive A.BY/SnJ mice develop chronic myocarditis based on virus persistence.

Connective tissue growth factor: a crucial cytokine-mediating cardiac fibrosis in ongoing enterovirus myocarditis.

Dilated cardiomyopathy (DCM) as a consequence of viral myocarditis is a worldwide cause of morbidity and death. The deposition of matrix proteins, such as collagen, in the course of ongoing viral myocarditis results in cardiac remodeling and finally in cardiac fibrosis, the hallmark of DCM. To identify mediators of virus-induced cardiac fibrosis, microarray analysis was conducted in a murine model of chronic coxsackievirus B3 (CVB3) myocarditis.

Sustained nitric oxide synthesis contributes to immunopathology in ongoing myocarditis attributable to interleukin-10 disorders.

Ongoing coxsackievirus B3 (CVB3) myocarditis is characterized by persistence of viral RNA and chronic inflammation primarily mediated by macrophages and T cells. Activated macrophages produce anti-viral effector molecules comprising reactive nitrogen intermediates; however, reactive nitrogen intermediates also contribute to host tissue damage. Controlled activation of macrophages depends on interferon (IFN)-gamma and interleukin (IL)-10.

Ongoing coxsackievirus myocarditis is associated with increased formation and activity of myocardial immunoproteasomes.

A growing body of evidence indicates that viral infections of the heart contribute to ongoing myocarditis and dilated cardiomyopathy. Murine models of coxsackievirus B3 (CVB3)-induced myocarditis mimic the human disease and allow identification of susceptibility factors that modulate the course of viral myocarditis. Susceptible mouse strains develop chronic myocarditis on the basis of restricted viral replication, whereas resistant strains recover after successful virus elimination.

Molecular pathology of inflammatory cardiomyopathy.

Endomyocardial biopsy (EMB) is often performed in patients presenting with sudden onset of heart failure to identify myocarditis. The introduction of immunohistochemical techniques for the detection and differentiation of infiltrating immune cells, specific adhesion molecules and MHC class I and II molecules increased the prognostic value of EMB in the diagnosis of myocarditis considerably. A major breakthrough in the understanding of pathogenetic mechanisms in myocarditis was achieved by diagnostic use of molecular biological methods.

beta2-microglobulin-associated regulation of interferon-gamma and virus-specific immunoglobulin G confer resistance against the development of chronic coxsackievirus myocarditis.

To gain insight into the strategies of the immune system to confer resistance against the development of chronic coxsackievirus B3 (CVB3) myocarditis we compared the course of the disease in C57BL/6 mice, beta2-microglobulin knockout (beta2m(-/-)) mice, and perforin-deficient (perforin(-/-)) mice. We found that perforin(-/-) mice as well as immunocompetent C57BL/6 mice reveal a resistant phenotype with complete elimination of the virus from the heart in the course of acute myocarditis. In contrast, myocardial CVB3 infection of beta2m(-/-) mice was characterized by a significantly higher virus load associated with a fulminant acute inflammatory response and, as a consequence of virus persistence, by the development of chronic myocarditis.