Viral diseases are a major threat to modern society and the global health system. It is therefore of utter relevance to understand the way viruses affect the host as a basis to find new treatment solutions. The understanding of viral
myocarditis (VMC) is incomplete and effective treatment options are lacking. This review will discuss the mechanism, effects, and treatment options of the most frequent
myocarditis-causing viruses namely enteroviruses such as Coxsackievirus B3 (CVB3) and Parvovirus B19 (PVB19) on the human heart. Thereby, we focus on: 1. Viral entry: CVB3 use Coxsackievirus-
Adenovirus-Receptor (CAR) and
Decay Accelerating Factor (DAF) to enter cardiac myocytes while PVB19 use the receptor globoside (Gb4) to enter cardiac endothelial cells. 2. Immune system responses: The innate immune system mediated by activated cardiac
toll-like receptors (TLRs) worsen
inflammation in CVB3-infected mouse hearts. Different types of cells of the adaptive immune system are recruited to the site of
inflammation that have either protective or adverse effects during VMC. 3. Autophagy: CVB3 evades autophagosomal degradation and misuses the autophasomal pathway for viral replication and release. 4. Viral replication sites: CVB3 promotes the formation of double membrane vesicles (DMVs), which it uses as replication sites. PVB19 uses the host cell nucleus as the replication site and uses the host cell DNA replication system. 5. Cell cycle manipulation: CVB3 attenuates the cell cycle at the G1/S phase, which promotes viral transcription and replication. PVB19 exerts cell cycle arrest in the S phase using its viral
endonuclease activity. 6. Regulation of apoptosis: Enteroviruses prevent apoptosis during early stages of
infection and promote cell death during later stages by using the
viral proteases 2A and 3C, and
viroporin 2B. PVB19 promotes apoptosis using the non-structural
proteins NS1 and the 11 kDa
protein. 7. Energy metabolism: Dysregulation of respiratory chain complex expression, activity and ROS production may be altered in CVB3- and PVB19-mediated
myocarditis. 8.
Ion channel modulation: CVB3-expression was indicated to alter
calcium and
potassium currents in Xenopus laevis oocytes and rodent cardiomyocytes. The
phospholipase 2-like activity of PVB19 may alter several
calcium,
potassium and
sodium channels. By understanding the general pathophysiological mechanisms of well-studied
myocarditis-linked viruses, we might be provided with a guideline to handle other less-studied human viruses.