Virus-Host Interactions of Enteroviruses and Parvovirus B19 in Myocarditis

Abstract

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.

RKIP suppresses the influenza A virus‑induced airway inflammatory response via the ERK/MAPK pathway

“…It has previously been demonstrated that airway inflammation is exacerbated and the cell cycle blocked after influenza virus infection ( 37 , 44 ), and a previous study reported that cell cycle arrest promoted viral replication to increase inflammation ( 44 ). The present study elucidated the role of RKIP in promoting recovery of the cell cycle after its arrest to alleviate the inflammatory responses induced by IAV in airway epithelial cells.…”

Mechanisms and Therapeutic Strategies of Viral Myocarditis Targeting Autophagy

“…Considering that autophagosomes are involved in the regulation of many important physiological processes, changes in autophagosome levels may also influence the development of viral myocarditis. Recent studies have shown that autophagy may influence the development of myocarditis by inhibiting viral replication, influencing cell apoptosis and inducing cellular immune responses ( Luo et al, 2010 ; Yoshida, 2017 ; Ho et al, 2021 ).…”

“…The local immune environment in cardiac tissues in viral myocarditis profoundly affects the progression of viral myocarditis, which can be divided into three main phases. The first phase is viral entry and innate immune system activation, the second phase is adaptive immune response activation, and the third phase is recovery or disease progression ( Ho et al, 2021 ).…”

“…Innate immune cells, including natural killer cells (NK cells), natural killer T cells (NKT cells), monocytes, macrophages, and dendritic cells, are recruited to the infected area by these cytokines. It is thought that the presence of NK and NKT cells is beneficial during the early phase of viral myocarditis, while other cells of the innate immune system appear to have a negative effect ( Ho et al, 2021 ).…”

“…The most severe tissue damage occurs in this phase due to high viral replication and inflammatory processes. There is increased release of the cytokines TNF, IL-1a, IL-1β, IL-2, and IFN-γ, as well as the recruitment of virus-specific T- and B-lymphocytes, accompanied by cellular and humoral antibodies to resist the infection ( Ho et al, 2021 ). Pathogen neutralization during the adaptive response is more complex than neutralization by the innate immune system, and its contribution to cardiac injury is more sophisticated ( Corsten et al, 2012 ).…”