A Kidnapping Story: How Coxsackievirus B3 and Its Host Cell Interact
Cellular Physiology and Biochemistry
Infections with Coxsackievirus B3 and other members of the enterovirus genus are a common reason for myocarditis and sudden cardiac death in modern society. Despite intensive scientific efforts to cure enterovirus infections, there is still no standardized treatment option. The complexity of Coxsackievirus B3´s effects on the host cell make well defined studies on this topic very challenging. However, recent publications report newly found effects of CVB3´s structural and non-structural
... on infected cells. For the first time, the viral capsid protein VP1 was shown to have direct influence on the viral life-cycle. By shortening the G0 and the G2 phase and simultaneously prolonging the G1 and G1-S phase, the translation of viral proteins is enhanced and the production of viable CVB3 particles is promoted. Coxsackievirus B3´s viroporin, protein 2B, was recently studied in more detail as well. Structural and physiological analyses identified two hydrophilic α-helices in the structure of 2B, enabling it to insert into cellular membranes of host cells. As main target of 2B the endoplasmatic reticulum was identified. The insertion of 2B into the ER membranes leads to an uncontrolled calcium outflow into the cytoplasm. Additional insertion of 2B into the cell membrane leads to host cell destabilization and in the end to release of viral progeny. The importance of the Coxsackievirus B3´s proteases 2A and 3C in pathogenicity is observed since years. Recently, DAP5 and eIf4G were identified as new cleavage targets for protease 2A. Cleavage of DAP-5 into DAP5-N and DAP5-C changes the gene expression of the host cell and promotes cell death. Additionally, protease 3C targets and cleaves procaspase 8 promoting the mitochondrial apoptosis pathway and cell death. Recent studies identified significant effects of CVB3 on mitochondria of infected cells. Mouse cardiomyocytes showed decreased activities of respiratory chain complexes I-III and changed transcription of important subunits of the complexes I-IV. A disrupted energy metabolism may be one of the main causes of cardiac insufficiency and death in CVB3 infected patients. In addition to a modified energy metabolism, CVB3 affects cardiac ion channels, KCNQ1 in particular. SGK1, which is an important Peischard et al.: CVB3 Host Cell Interaction mediator in KCNQ1 membrane insertions, is highly upregulated during CVB3 infections. This results in an increased insertion of KCNQ1 into the cell membrane of cardiac cells. Under stress conditions, this KCNQ1 overshoot may lead to a disturbed cardiac action potential and therefore to sudden cardiac death, as it is often observed in CVB3 infected persons. Bax 72 hours post transfection. The resulting imbalance of Bax and Bcl-2 may contribute to apoptotic function of protease 2A and 3C of CVB3. CVB3 and its interactions with mitochondria In a murine model it was shown, that CVB3 impacts mitochondrial respiratory chain and the energy metabolism of cardiomyocytes. An additional imbalance of Drp1 and Fis1 leads to increased mitochondrial fission and cell death. Fig. 4. A: 3D Model of CVB3 Protease 2A. B: 3D Model of CVB3 Protease 3C. C: Function of proteases 2A and 3C in the host-cell. Protease 2A is responsible for the cleavage of elF4G and so suppresses host-cell translation. Cleavage of DAP5 by CVB3 2A leads to the byproducts DAP5-N and DAP5-C, which suppress the transcription of anti-apoptotic genes and support the transcription of pro-apoptotic genes. Protease 3C cleaves and activates procaspase 8. Furthermore it supports the expression of Bax. Both effects lead to mitochondrial degradation and cell-death.