sCAR-Fc (Soluble Receptor Analogue) is an experimental prophylactic treatment against coxsackievirus B3 (CVB) infections. Coxsackievirus B3 can cause cardiac damage, eventually resulting in a weakened and enlarged heart that is termed dilated cardiomyopathy.[1] While many other treatments inhibit viral proliferation in myocytes, sCAR-Fc prevents the virus entering the cell by competitively binding to coxsackie virus and adenovirus receptors (CAR) on the membrane of myocytes.
| SCAR-Fc | |
|---|---|
| Other names | Soluble receptor analogue |
Myocarditis
editCoxsackievirus B3 is a single-stranded RNA enterovirus and a member of the Picornavirdae family.[1][2] Once the virus penetrates the host's systemic circulation via contaminated water or food, it can travel and infect the heart and cause myocarditis. Myocarditis is an inflammation of the heart, most commonly cause by viral infections. Amongst the viruses capable of causing myocarditis, CVB3 is a common agent identified in inducing cardiac damage. Internalization of the virus into myocytes occurs by binding to coxsackievirus-adenovirus receptors (CAR) located in tight junctions on cell membranes.[1][3] Once inside the cytoplasm, the virus can use the host's ribosomal machinery to proliferate and replicate progenies for further infection.[4] Extensive cardiac necrosis can occur by day three after infection as incubated viruses lyse myocytes, resulting in severe and rapid cardiac decompensation. With loss of cardiac cells increasing progressively, infected individual will experience abnormalities in left ventricular systolic and diastolic function, as well as electrical conduction defects manifesting as cardiac dysrhythmias.[5] As a result, ejection fraction decreases substantially.[5] The cytolytic destruction of heart cells can lead to dilated cardiomyopathy if not treated appropriately.[citation needed]
The role of the immune system in response to the presence of a virus has both beneficial and detrimental effects on the cardiac system.[1] The arrival of natural killer cells (NK cells) at the site of infection limits viral proliferation in myocytes. Conversely, while certain cytokines released from immune cells have protective effects, others such as tumor necrosis factor-alpha (TNFα) have deleterious effects on heart cells. Moreover, peak concentrations of T cells in the myocardium during days 7-14 play important roles in both viral clearance and immune mediated cardiac damage. T-cells not only lyse and destroy infected myocytes, but due to molecular mimicry, they also destroy normal, healthy cardiac cells, further driving the heart towards dilated cardiomyopathy.[6]
Mechanism
editA synthetic and soluble form of CAR (sCAR) has been created to prevent viral infection with CVB3. Attaching Fc domain of immunoglobulin IgG1 to sCAR (sCAR-Fc) enhances solubility and extends its half-life.[1][7] Furthermore, once sCAR-Fc binds the virus, macrophages and other phagocytic immune cells with Fc receptor recognition bind to the sCAR-Fc-viral complex to eliminate the virus. Essentially, sCAR-Fc mimics CAR receptors on cardiac cells, competitively inhibiting viral attachment and entry into myocytes. Decreased lesions in cardiac tissues, reduced cell necrosis, and diminished inflammatory responses are observed in sCAR-Fc treated cells (CITE). This suggests protective effects against myocardial damage by CVB3.[citation needed]
Conformational changes in a viral particle (A-particle) with sCAR-Fc-virus binding causing the loss of the virus’ internal capsid protein, VP4.[2] This irreversible reaction prevents the virus from interacting with cellular receptors (CAR) on cardiac cells, decreasing infectivity of CVB3.[8]
Administration
editAdministration of sCAR-Fc beyond three days after initial exposure to the virus does not have any beneficial effects as cardiac damage is too severe.[2] As such, the use of sCAR-Fc is currently limited to prophylactic treatments.[citation needed]
References
edit- ^ a b c d e Werk D, Pinkert S, Heim A, et al. (September 2009). "Combination of soluble coxsackievirus-adenovirus receptor and anti-coxsackievirus siRNAs exerts synergistic antiviral activity against coxsackievirus B3". Antiviral Res. 83 (3): 298–306. doi:10.1016/j.antiviral.2009.07.002. PMID 19591879.
- ^ a b c Goodfellow IG, Evans DJ, Blom AM, et al. (September 2005). "Inhibition of coxsackie B virus infection by soluble forms of its receptors: binding affinities, altered particle formation, and competition with cellular receptors". J. Virol. 79 (18): 12016–24. doi:10.1128/JVI.79.18.12016-12024.2005. PMC 1212587. PMID 16140777.
- ^ Yanagawa B, Spiller OB, Proctor DG, et al. (April 2004). "Soluble recombinant coxsackievirus and adenovirus receptor abrogates coxsackievirus b3-mediated pancreatitis and myocarditis in mice". J. Infect. Dis. 189 (8): 1431–9. doi:10.1086/382598. PMID 15073680.
- ^ Woodruff JF (November 1980). "Viral myocarditis. A review". Am. J. Pathol. 101 (2): 425–84. PMC 1903609. PMID 6254364.
- ^ a b Onyimba JA, Coronado MJ, Garton AE, et al. (2011). "The innate immune response to coxsackievirus B3 predicts progression to cardiovascular disease and heart failure in male mice". Biol Sex Differ. 2: 2. doi:10.1186/2042-6410-2-2. PMC 3049118. PMID 21338512.
- ^ Herzum M, Ruppert V, Küytz B, Jomaa H, Nakamura I, Maisch B (July 1994). "Coxsackievirus B3 infection leads to cell death of cardiac myocytes". J. Mol. Cell. Cardiol. 26 (7): 907–13. doi:10.1006/jmcc.1994.1108. PMID 7966359.
- ^ Fechner H, Pinkert S, Geisler A, Poller W, Kurreck J (2011). "Pharmacological and biological antiviral therapeutics for cardiac coxsackievirus infections". Molecules. 16 (10): 8475–503. doi:10.3390/molecules16108475. PMC 6264230. PMID 21989310.
- ^ Milstone AM, Petrella J, Sanchez MD, Mahmud M, Whitbeck JC, Bergelson JM (January 2005). "Interaction with coxsackievirus and adenovirus receptor, but not with decay-accelerating factor (DAF), induces A-particle formation in a DAF-binding coxsackievirus B3 isolate". J. Virol. 79 (1): 655–60. doi:10.1128/JVI.79.1.655-660.2005. PMC 538729. PMID 15596863.