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Myocarditis as systemic disease: new perspectives on pathogenesis
C M Carthy1, D Yang, D R Anderson
1Department of Pathology and Laboratory Medicine, University of British Columbia, St Paul's Hospital, Vancouver, Canada.
Insights
Coxsackie B viruses (CVB) can cause myocarditis and potentially lead to dilated cardiomyopathy. This study explores how CVB3 infects heart and immune cells, potentially hindering the immune response and viral clearance.
Area of Science:
- Virology
- Immunology
- Cardiology
Background:
- Myocarditis, an inflammation of the heart muscle, can be an early sign of or lead to dilated cardiomyopathy.
- Coxsackie B viruses (CVB), particularly CVB3, are common viral agents implicated in myocarditis.
- The pathogenesis of CVB3-induced myocarditis involves direct myocyte damage and immunopathological mechanisms.
Purpose of the Study:
- To investigate the pathogenesis of CVB3-induced myocarditis.
- To explore the interaction between CVB3 and immune cells.
- To understand the role of viral translation mechanisms in disease progression.
Main Methods:
- In situ hybridization and gene amplification to detect viral RNA persistence.
- Terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) to assess cell death.
- Analysis of viral internal ribosome entry site (IRES) function.
Main Results:
- CVB3 infection leads to non-apoptotic injury in cardiac tissue, with apoptotic bodies primarily from immune cells.
- CVB3 infects and persists in immune cells, localizing to splenic and lymph node follicles.
- CVB3 may perturb the immune response, potentially delaying viral clearance and influencing disease severity.
- CVB3 utilizes an internal ribosome entry site (IRES) for translation, arresting host cell translation to favor viral replication.
Conclusions:
- CVB3 infection of heart and immune cells contributes to myocarditis and potentially dilated cardiomyopathy.
- The virus-host-immune cell interaction is complex and influences disease outcome.
- Viral translation mechanisms, such as IRES, play a role in viral replication and pathogenesis.
Abstract:
1. Myocarditis may be an early indicator of or may subsequently lead to dilated cardiomyopathy in humans. This hypothesis has evolved from research on viruses that induce myocarditis, wherein the coxsackie B group viruses (CVB) in the family Picornaviridae are the most common known viral infectants of heart muscle. 2. Many competing hypotheses exist as to the pathogenesis of CVB3-induced myocarditis, including direct virus-induced myocyte damage and immunopathological disease with autoimmune sequelae. Evidence to support the direct-damage and viral RNA-persistence hypothesis is derived from in situ hybridization and gene amplification studies. 3. Recent use of terminal deoxynucleotidyl transferase-mediated nick-end labelling indicates that this injury in target organs is largely non-apoptotic in nature. Most apoptotic bodies in cardiac tissue are derived from immune cells. 4. Beyond infection of heart muscle, CVB3 can also associate with, infect and persist in cells of immune origin. The CVB3 localizes to follicles in spleens and lymph nodes of the murine host and this particular localization may continue in mice susceptible to more aggressive myocarditis. Whether virus-immune cell association in these compartments is advantageous (or essential) to the host in the evolution of anti-viral immune responses or whether it is more advantageous to the virus in immunosuppression of the host is not known. 5. We suggest that CVB3 can directly perturb or alter the immune response, thereby delaying viral clearance from vulnerable systemic organs. Both host and viral genetic factors can influence susceptibility, persistence and disease progression. 6. Picornaviruses use a unique method for the initiation of translation, involving the internal binding of the ribosome on a sequence element of the 5' untranslated region, termed an internal ribosome entry site (IRES). 7. The IRES of CVB3 is located at approximately stem loops G, H and I, spanning nucloetides 530 and 630. Arrest of host translation is also a feature of picornavirus infection. Such regulation of host cell translation machinery no doubt fosters viral replication at the expense of the host cell. 8. Differences between cell types in the mechanisms, along with those at other key steps in the viral life cycle and in signalling via kinase pathways, may determine viral tropism and cellular destruction and the physiological outcome of neighbouring cells.