Viral myocarditis
Citations
All
Search in:AllTitleAbstractAuthor name
Publications
(14)
Patents
Grants
Pathways
Clinical trials
Publication
Journal: New England Journal of Medicine
April/14/2009
Publication
Journal: Cell
March/1/2006
Abstract
Group B coxsackieviruses (CVBs) must cross the epithelium as they initiate infection, but the mechanism by which this occurs remains uncertain. The coxsackievirus and adenovirus receptor (CAR) is a component of the tight junction and is inaccessible to virus approaching from the apical surface. Many CVBs also interact with the GPI-anchored protein decay-accelerating factor (DAF). Here, we report that virus attachment to DAF on the apical cell surface activates Abl kinase, triggering Rac-dependent actin rearrangements that permit virus movement to the tight junction. Within the junction, interaction with CAR promotes conformational changes in the virus capsid that are essential for virus entry and release of viral RNA. Interaction with DAF also activates Fyn kinase, an event that is required for the phosphorylation of caveolin and transport of virus into the cell within caveolar vesicles. CVBs thus exploit DAF-mediated signaling pathways to surmount the epithelial barrier.
Publication
Journal: Circulation
March/17/1999
Abstract
A progression from viral myocarditis to dilated cardiomyopathy has long been hypothesized, but the actual extent of this progression has been uncertain. However, a causal link between viral myocarditis and dilated cardiomyopathy has become more evident than before with the tremendous developments in the molecular analyses of autopsy and endomyocardial biopsy specimens, new techniques of viral gene amplification, and modern immunology. The persistence of viral RNA in the myocardium beyond 90 days after inoculation, confirmed by the method of polymerase chain reaction, has given us new insights into the pathogenesis of dilated cardiomyopathy. Moreover, new knowledge of T-cell-mediated immune responses in murine viral myocarditis has contributed a great deal to the understanding of the mechanisms of ongoing disease processes. Apoptotic cell death may provide the third concept to explain the pathogenesis of dilated cardiomyopathy, in addition to persistent viral RNA in the heart tissue and an immune system-mediated mechanism. Beneficial effects of alpha1-adrenergic blocking agents, carteolol, verapamil, and ACE inhibitors have been shown clinically and experimentally in the treatment of viral myocarditis and dilated cardiomyopathy. Antiviral agents should be more extensively investigated for clinical use. The rather discouraging results obtained to date with immunosuppressive agents in the treatment of viral myocarditis indicated the importance of sparing neutralizing antibody production, which may be controlled by B cells, and raised the possibility of promising developments in immunomodulating therapy.
Authors
Publication
Journal: Annual Review of Pathology: Mechanisms of Disease
May/12/2008
Abstract
Myocarditis is a cardiac disease associated with inflammation and injury of the myocardium. Several viruses have been associated with myocarditis in humans. However, coxsackievirus B3 is still considered the dominant etiological agent. The observed pathology in viral myocarditis is a result of cooperation or teamwork between viral processes and host immune responses at various stages of disease. Both innate and adaptive immune responses are crucial determinants of the severity of myocardial damage, and contribute to the development of chronic myocarditis and dilated cardiomyopathy following acute viral myocarditis. Advances in genomics and proteomics, and in the use of informatics and biostatistics, are allowing unbiased initial evaluations that can be the basis for testable hypotheses about virus pathogenesis and new therapies.
Publication
Journal: Circulation
September/12/2001
Publication
Journal: Canadian Journal of Physiology and Pharmacology
August/22/2006
Abstract
The cellular biological function of the ubiquitin-proteasome pathway as a major intracellular protein degradation pathway, and as an important modulator for the regulation of many fundamental cellular processes has been greatly appreciated over the last decade. The critical role of the ubiquitin-proteasome pathway in viral pathogenesis has become increasingly apparent. Many viruses have been reported to evolve different strategies to utilize the ubiquitin-proteasome pathway for their own benefits. Here, we review the general background and function of the ubiquitin-proteasome pathway, summarize our current understanding of how viruses use this pathway to target cellular proteins, and finally, discuss the roles of this pathway in enteroviral infection, and the potential therapeutic application of proteasome inhibition in myocarditis.
Publication
Journal: Cardiovascular Research
December/14/2003
Abstract
Myocarditis is a complex disease because multiple pathogenetic mechanisms play a role. While these mechanisms appear to act in a chronological cascade, they undoubtedly overlap in some cases, rendering diagnosis and treatment difficult. Ultimately, dilated cardiomyopathy (DCM) may result. A multitude of still-circumstantial evidence points to a major role of viral myocarditis in the etiology of DCM. The common presence of viral genetic material and viral proteins in the myocardium of patients with DCM provides the most compelling evidence, but proof of causality is still lacking. Nevertheless, because of the striking increase in heart failure prevalence in recent years, anti-viral and anti-inflammatory therapies should be developed for their potential to prevent or ameliorate DCM.
Publication
Journal: Viral Immunology
September/27/2006
Abstract
Coxsackievirus (CVB) infection is a significant cause of myocarditis and dilated cardiomyopathy (DCM). Heart disease may be caused by direct cytopathic effects of the virus, a pathologic immune response to persistent virus, or autoimmunity triggered by the viral infection. CVB interacts with its host at multiple stages during disease development. Signaling through viral receptors may alter the intracellular environment in addition to facilitating virus entry. Viral genetic determinants that encode cardiovirulence have been mapped and may change depending on the nutritional status of the host. Virus persistence is directly associated with pathology, and recent work demonstrates that CVB evolves into a slowly replicating form capable of establishing a low-grade infection in the heart. The innate immune response to CVB has taken on increasing importance because of its role in shaping the development of the adaptive immune response that is responsible for cardiac pathology. Studies of T cell responsiveness and the development of autoimmunity at the molecular level are beginning to clarify the mechanisms through which CVB infection causes inflammatory heart disease.
Pulse
Views:
1
Posts:
No posts
Rating:
Not rated
Publication
Journal: Current Topics in Microbiology and Immunology
May/18/2008
Abstract
Coxsackievirus infection has been demonstrated to be a cause of acute and fulminant viral myocarditis and has been associated with dilated cardiomyopathy. While considerable attention has focused on the role of the cellular and humoral, antigen-specific immune system in viral myocarditis, the interaction between the virus and the infected host myocyte is also important. Coxsackievirus has a relative tropism for the heart that is in part mediated by relatively high levels of the coxsackievirus and adenovirus receptor (CAR) on the cardiac myocyte. Once within the myocyte, coxsackievirus produces proteases, such as protease 2A, that have an important role in viral replication, but can also affect host cell proteins such as dystrophin. Cleavage of dystrophin may have a role in release of the virus from the myocyte since viral infection is increased in the absence of dystrophin. In addition to the direct effect of viral proteins on cardiac myocytes, there is now evidence that the cardiac myocyte has a potent innate immune defense against coxsackieviral infection. Suppressors of cytokine signaling (SOCS) can inhibit an interferon-independent mechanism within the cardiac myocyte. In summary, the interaction between coxsackievirus and the infected myocyte has a significant role in the pathogenesis of viral myocarditis and the susceptibility to viral infection.
Publication
Journal: Circulation
January/28/2007
Publication
Journal: Medical Microbiology and Immunology
July/26/2004
Abstract
Genetic defects of the dystrophin-glycoprotein complex (DGC) cause hereditary dilated cardiomyopathy. Enteroviruses can also cause cardiomyopathy and we have previously described a mechanism involved in enterovirus-induced dilated cardiomyopathy: The enteroviral protease 2A directly cleaves dystrophin in the hinge 3 region, leading to functional dystrophin impairment. During infection of mice with coxsackievirus B3, the DGC in the heart is disrupted and the sarcolemmal integrity is lost in virus-infected cardiomyocytes. Additionally, dystrophin deficiency markedly increases enterovirus-induced cardiomyopathy in vivo, suggesting a pathogenetic role of the dystrophin cleavage in enterovirus-induced cardiomyopathy. Here, we extend these experimental findings to a patient with dilated cardiomyopathy due to a coxsackievirus B2 myocarditis. Endomyocardial biopsy specimens showed an inflammatory infiltrate and myocytolysis. Immunostaining for the enteroviral capsid antigen VP1 revealed virus-infected cardiomyocytes. Focal areas of cardiomyocytes displayed a loss of the sarcolemmal staining pattern for dystrophin and beta-sarcoglycan identical to previous findings in virus-infected mouse hearts. In vitro, coxsackievirus B2 protease 2A cleaved human dystrophin. These findings demonstrate that in human coxsackievirus B myocarditis a focal disruption of the DGC can principally occur and may contribute to the pathogenesis of human enterovirus-induced dilated cardiomyopathy.
Publication
Journal: Herz
March/6/2003
Abstract
BACKGROUND
Inflammatory processes induced by rival infection are believed to be one of the major pathogenetic mechanisms in inflammatory dilated cardiomyopathy. Although the reason for progression to myocardial failure is not fully understood, postulated mechanisms include persistent viral infection alone or in combination with autoimmune processes.
METHODS
Murine models of myocarditis have provided insight into the mechanisms by which autoimmune responses to cardiac antigens, probably in response to viral infection of the myocardium, arise and cause tissue pathology. Organ-specificity, cross-reactivity between microbial agents and cardiac tissue, and induction of tolerance to self-antigen are issues still at stake. In addition, cytokines mediate activation and effector phase of innate and specific immunity, which are both important in controlling viral infection. The innate immune response not only has an important protective function but also serves to initiate and regulate subsequent specific immune responses. In man, on the one hand specific T cells and antibodies against different cardiac tissue components have been demonstrated in myocardium and sera of patients with inflammatory cardiomyopathy, and on the other hand viral genome has been identified in endomyocardial biopsies due to the rapid development of new molecular biological techniques such as polymerase chain reaction (PCR), southern blot analysis and in-situ hybridization. But it is still a mater of debate whether virus infection itself, the ensuing immune response, or both, contribute to the deterioration of left ventricular function.
CONCLUSIONS
Taking these mechanisms into account, screening for viral genome by PCR and detection of inflammatory infiltrates by immunohistochemistry are considered crucial for the establishment of a definite diagnosis thereby allowing for the initiation of specific therapeutic strategies.
Publication
Journal: Herz
October/1/2000
Abstract
Genetic deficiency of the dystrophin-glycoprotein complex causes hereditary dilated cardiomyopathy. Enteroviruses can also cause cardiomyopathy and we have recently described a potential molecular mechanism for enterovirus-induced dilated cardiomyopathy. The coxsackieviral protease 2A proteolytically cleaves and functionally impairs dystrophin. Additionally, during infection with coxsackievirus B3, the dystrophin-glycoprotein complex becomes disrupted and the sarcolemmal integrity is lost. This review article discusses the importance of the dystrophin cleavage for the development of increased sarcolemmal permeability and potential pathways for mechanisms by which the dystrophin cleavage during coxsackieviral infection may contribute to dilated cardiomyopathy.
Publication
Journal: Journal of Cardiovascular Medicine
October/29/2008
Abstract
Myocarditis is an inflammatory heart muscle disease, resulting from various etiologies, both noninfectious and infectious, which may be associated or not with cardiac dysfunction. Its course is unpredictable: it may spontaneously resolve or evolve into dilated cardiomyopathy and heart failure. A possible connection between myocarditis and dilated cardiomyopathy has long been postulated, but the intimate mechanisms linking these two conditions are still poorly understood. Viral myocarditis could induce a dilated cardiomyopathy through viral persistence and/or by triggering an autoimmune process. Understanding the mechanisms underlying the relationship between myocarditis and dilated cardiomyopathy will help in identifying an effective strategy of treatment aimed to stop and prevent cardiac damage. Specifically, we need to (a) evaluate the potential role of autoantibodies in disease prevention and progression, and understand their importance as markers of disease progression; (b) clarify the role of immunoregulation in exacerbating the disease.