Abstract
Viral myocarditis is an inflammation of the heart muscle triggered by direct virus-induced cytolysis and immune response mechanisms with most severe consequences during early childhood. Acute and long-term manifestation of damaged heart tissue and disturbances of cardiac performance involve virus-triggered adverse activation of the immune response and both immunopathology, as well as, autoimmunity account for such immune-destructive processes. It is a matter of ongoing debate to what extent subclinical virus infection contributes to the debilitating sequela of the acute disease. In this review, we conceptualize the many functions of the proteasome in viral myocarditis and discuss the adaptation of this multi-catalytic protease complex together with its implications on the course of disease. Inhibition of proteasome function is already highly relevant as a strategy in treating various malignancies. However, cardiotoxicity and immune-related adverse effects have proven significant hurdles, representative of the target's wide-ranging functions. Thus, we further discuss the molecular details of proteasome-mediated activity of the immune response for virus-mediated inflammatory heart disease. We summarize how the spatiotemporal flexibility of the proteasome might be tackled for therapeutic purposes aiming to mitigate virus-mediated adverse activation of the immune response in the heart.
Highlights
Myocarditis and its debilitating sequela, inflammatory cardiomyopathy, are leading causes of heart failure and sudden cardiac death in infants, children, and young adults [1] with viral infections being the most common trigger of non-ischemic myocardial inflammation in the Western world [2]
Most of our knowledge on the pathology of viral myocarditis comes from infection with enteroviruses, in particular coxsackievirus B3 (CVB3) in mice
Since this review mainly focuses on the immunomodulatory function of the proteasome complex itself during manifestation of virus-mediated inflammatory damage of heart tissue, the reader is encouraged to refer to an excellent review recently provided by Honglin Luo on interactions between ubiquitin/ubiquitin family proteins and viral growth [68]
Summary
Myocarditis and its debilitating sequela, inflammatory cardiomyopathy, are leading causes of heart failure and sudden cardiac death in infants, children, and young adults [1] with viral infections being the most common trigger of non-ischemic myocardial inflammation in the Western world [2]. There are numerous examples for viral, bacterial, and parasitic pathogens for which in vitro peptide processing studies revealed facilitated MHC class I epitope liberation by the i-proteasome complex in comparison to lower epitope abundance upon processing of model polypeptides with the standard proteasome [39] This altered prevalence of antigenic peptide generation by the i-proteasome is attributed to different peptide cleavage site usage [40], and can elicit to altered CD8+ T cell-mediated immune surveillance [41,42,43,44,45,46]. Since i-proteasome activity controls alloantibody production by B cells and influences processes resulting in T cell exhaustion, i-proteasome-selective compounds could be used to prevent allograft rejection upon organ transplantation as well [65, 66] All these recent reports shed light onto several previously unappreciated biological functions of the i-proteasome and support the requirement for a detailed overview on the pathological function of the proteasome during virus-induced inflammatory heart tissue injury. The human cytomegalovirus (HCMV) pp protein stimulates quiescent cells to enter the cell cycle by targeting
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
