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←Created page with ''''sCAR-Fc''' (a '''Soluble Receptor Analogue''') are experimental prophylactic treatments against coxsackievirus B3 infections. Coxsackievirus B3 can cause card...'
 
whole lotta fixing, most of these are freely available hence should be linked as such, cleanup of multiple
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'''sCAR-Fc''' (a '''Soluble Receptor Analogue''') are experimental prophylactic treatments against coxsackievirus B3 infections. Coxsackievirus B3 can cause cardiac damage, eventually resulting in [[dilated cardiomyopathy]] <ref name="a">Werk, Denise, Sandra Pinkert, Albert Heim, Heinz Zeichhardt, Hans-Peter Grunert, Wolfgang Poller, Volker A. Erdmann, Henry Fechner, and Jens Kurreck. "Combination of soluble coxsackievirus-adenovirus receptor and anti-coxsackievirus siRNAs exerts synergistic antiviral activity against coxsackievirus B3." Antiviral Research 83 (2009): 298-306</ref> . While many other treatments inhibit viral proliferation in myocytes, sCAR-Fc prevents entry of virus into cell by competitively binding to [[coxsackie virus and adenovirus receptor]] (CAR) located on membrane of myocytes.
'''sCAR-Fc''' ('''Soluble Receptor Analogue''') are experimental prophylactic treatments against [[Cxsackievirus]] B3 (CVB) infections. Coxsackievirus B3 can cause cardiac damage, eventually resulting in [[dilated cardiomyopathy]].<ref name="a">{{cite journal |author=Werk D, Pinkert S, Heim A, ''et al.'' |title=Combination of soluble coxsackievirus-adenovirus receptor and anti-coxsackievirus siRNAs exerts synergistic antiviral activity against coxsackievirus B3 |journal=Antiviral Res. |volume=83 |issue=3 |pages=298–306 |year=2009 |month=September |pmid=19591879 |doi=10.1016/j.antiviral.2009.07.002 }}</ref> While many other treatments inhibit viral proliferation in [[myocyte]]s, sCAR-Fc prevents entry of virus into cell by competitively binding to [[coxsackie virus and adenovirus receptor]] (CAR) located on the membrane of myocytes.


==Myocarditis==
==CBV and myocarditis==
Coxsackievirus B3 (CVB) is a single stranded RNA [[enterovirus]] and a member of the [[picornavirus]] family <ref name="a" /> <ref name="c">Goodfellow, I. G., D. J. Evans, A. M. Blom, D. Kerrigan, J. S. Miners, B. P. Morgan, and O. B. Spiller. "Inhibition of Coxsackie B Virus Infection by Soluble Forms of Its Receptors: Binding Affinities, Altered Particle Formation, and Competition with Cellular Receptors." Journal of Virology 79 (2005): 12016-2024.</ref>. 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 <ref name="a" /> <ref>Yanagawa, Bobby, O. Brad Spiller, David G. Proctor, Jonathan Choy, Honglin Luo, Huifang M. Zhang, Agripina Suarez, Decheng Yang, and Bruce M. McManus. "Soluble Recombinant Coxsackievirus and Adenovirus Receptor Abrogates Coxsackievirus B3–Mediated Pancreatitis and Myocarditis in Mice." The Journal of Infectious Diseases 189 (2004): 1431-439.</ref>. Once inside the cytoplasm, the virus can use the host’s ribosomal machinery to proliferate and replicate progenies for further infection <ref>Woodruff, Jack F. “ Viral Myocarditis”. American Journal of Pathology 101(1980): 425-484.</ref>. 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]]<ref name="b">Onyimba, Jennifer A., Michael J. Coronado, Amanda E. Garton, Joseph B. Kim, Adriana Bucek, Djahida Bedja, Kathleen L. Gabrielson, Tomas R. Guilarte, and DeLisa Fairweather. "The innate immune response to coxsackievirus B3 predicts progression to cardiovascular disease and heart failure in male mice." Biology of Sex Differences 2 (2011): 2.</ref>. As a result, [[ejection fraction]] decreases substantially <ref name="b" />. The cytolytic destruction of heart cells can subsequently lead to dilated cardiomyopathy if not treated appropriately.
Coxsackievirus B3 is a single stranded RNA [[enterovirus]] and a member of the [[picornavirus]] family.<ref name="a" /><ref name="c">{{cite journal |author=Goodfellow IG, Evans DJ, Blom AM, ''et al.'' |title=Inhibition of coxsackie B virus infection by soluble forms of its receptors: binding affinities, altered particle formation, and competition with cellular receptors |journal=J. Virol. |volume=79 |issue=18 |pages=12016–24 |year=2005 |month=September |pmid=16140777 |pmc=1212587 |doi=10.1128/JVI.79.18.12016-12024.2005}}</ref> 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 junction]]s on cell membranes.<ref name="a" /><ref>{{cite journal |author=Yanagawa B, Spiller OB, Proctor DG, ''et al.'' |title=Soluble recombinant coxsackievirus and adenovirus receptor abrogates coxsackievirus b3-mediated pancreatitis and myocarditis in mice |journal=J. Infect. Dis. |volume=189 |issue=8 |pages=1431–9 |year=2004 |month=April |pmid=15073680 |doi=10.1086/382598}}</ref> Once inside the cytoplasm, the virus can use the host's ribosomal machinery to proliferate and replicate progenies for further infection.<ref>{{cite journal |author=Woodruff JF |title=Viral myocarditis. A review |journal=Am. J. Pathol. |volume=101 |issue=2 |pages=425–84 |year=1980 |month=November |pmid=6254364 |pmc=1903609}}</ref> 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]].<ref name="b">{{cite journal |author=Onyimba JA, Coronado MJ, Garton AE, ''et al.'' |title=The innate immune response to coxsackievirus B3 predicts progression to cardiovascular disease and heart failure in male mice |journal=Biol Sex Differ |volume=2 |issue= |pages=2 |year=2011 |pmid=21338512 |pmc=3049118 |doi=10.1186/2042-6410-2-2 }}</ref> As a result, [[ejection fraction]] decreases substantially.<ref name="b" /> The cytolytic destruction of heart cells can subsequently lead to dilated cardiomyopathy if not treated appropriately.


The role of the immune system in response to the presence of a virus has both beneficial and detrimental effects on the cardiac system <ref name="a" />. 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 <ref>Herzum, Matthias, Volker Ruppert, Barbara Kuytz, Hassan Jomaa, Izuro Nakamura, and Bernhard Maisch. "Coxsackievirus B3 Infection Leads to Cell Death of Cardiac Myocytes." Journal of Molecular Cell Cardiology 26 (1994): 907-13.</ref>.
The role of the immune system in response to the presence of a virus has both beneficial and detrimental effects on the cardiac system.<ref name="a" /> 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.<ref>{{cite journal |author=Herzum M, Ruppert V, Küytz B, Jomaa H, Nakamura I, Maisch B |title=Coxsackievirus B3 infection leads to cell death of cardiac myocytes |journal=J. Mol. Cell. Cardiol. |volume=26 |issue=7 |pages=907–13 |year=1994 |month=July |pmid=7966359 |doi=10.1006/jmcc.1994.1108 }}</ref>


==Mechanism of sCAR-Fc==
==Mechanism ==
A 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]]<ref>Fechner, Henry, Sandra Pinkert, Anja Geisler, Wolfgang Poller, and Jens Kurreck. "Pharmacological and Biological Antiviral Therapeutics for Cardiac Coxsackievirus Infections." Molecules 16 (2011): 8475-503.</ref> <ref name="a" />. 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.
A 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]].<ref>{{cite journal |author=Fechner H, Pinkert S, Geisler A, Poller W, Kurreck J |title=Pharmacological and biological antiviral therapeutics for cardiac coxsackievirus infections |journal=Molecules |volume=16 |issue=10 |pages=8475–503 |year=2011 |pmid=21989310 |doi=10.3390/molecules16108475}}</ref><ref name="a" /> 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.
Conformational changes in a viral particle (A-particle) with sCAR-Fc-virus binding causing the loss of the virus’ internal [[capsid]] protein, VP4 <ref name="c" />. This irreversible reaction prevents the virus from interacting with cellular receptors (CAR) on cardiac cells, decreasing infectivity of CVB3<ref>Mistone, Aaron M., JenniElizabeth Petrella, Melissa D. Sanchez, Mariam Mahmud, J. C. Whitbeck, and Jeffrey M. Bergelson. "A-Particle Formation in a DAF-Binding Decay-Accelerating Factor (DAF), Induces Adenovirus Receptor, but Not with Interaction with Coxsackievirus and Coxsackievirus B3 Isolate." Journal of Virology 79 (2005): 655.</ref>.
Conformational changes in a viral particle (A-particle) with sCAR-Fc-virus binding causing the loss of the virus’ internal [[capsid]] protein, VP4.<ref name="c" /> This irreversible reaction prevents the virus from interacting with cellular receptors (CAR) on cardiac cells, decreasing infectivity of CVB3.<ref>{{cite journal |author=Milstone AM, Petrella J, Sanchez MD, Mahmud M, Whitbeck JC, Bergelson JM |title=Interaction with coxsackievirus and adenovirus receptor, but not with decay-accelerating factor (DAF), induces A-particle formation in a DAF-binding coxsackievirus B3 isolate |journal=J. Virol. |volume=79 |issue=1 |pages=655–60 |year=2005 |month=January |pmid=15596863 |pmc=538729 |doi=10.1128/JVI.79.1.655-660.2005}}</ref>


==Discussion==
==Discussion==
Administration of sCAR-Fc beyond 3 days after initial exposure to the virus does not have any beneficial effects as cardiac damage is too severe <ref name="c" />. As such, the use of sCAR-Fc is currently limited to prophylactic treatments.
Administration of sCAR-Fc beyond 3 days after initial exposure to the virus does not have any beneficial effects as cardiac damage is too severe.<ref name="c" /> As such, the use of sCAR-Fc is currently limited to prophylactic treatments.


==References==
==References==


{{Reflist}}
{{Reflist}}


Revision as of 03:00, 21 March 2012

sCAR-Fc (Soluble Receptor Analogue) are experimental prophylactic treatments against Cxsackievirus B3 (CVB) infections. Coxsackievirus B3 can cause cardiac damage, eventually resulting in dilated cardiomyopathy.[1] While many other treatments inhibit viral proliferation in myocytes, sCAR-Fc prevents entry of virus into cell by competitively binding to coxsackie virus and adenovirus receptor (CAR) located on the membrane of myocytes.

Myocarditis

Coxsackievirus B3 is a single stranded RNA enterovirus and a member of the picornavirus 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 subsequently lead to dilated cardiomyopathy if not treated appropriately.

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

A 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.[7][1] 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.

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]

Discussion

Administration of sCAR-Fc beyond 3 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.

References

  1. ^ a b c d e Werk D, Pinkert S, Heim A; et al. (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. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  2. ^ a b c Goodfellow IG, Evans DJ, Blom AM; et al. (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. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  3. ^ Yanagawa B, Spiller OB, Proctor DG; et al. (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. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  4. ^ Woodruff JF (1980). "Viral myocarditis. A review". Am. J. Pathol. 101 (2): 425–84. PMC 1903609. PMID 6254364. {{cite journal}}: Unknown parameter |month= ignored (help)
  5. ^ 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. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  6. ^ Herzum M, Ruppert V, Küytz B, Jomaa H, Nakamura I, Maisch B (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  7. ^ 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. PMID 21989310.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  8. ^ Milstone AM, Petrella J, Sanchez MD, Mahmud M, Whitbeck JC, Bergelson JM (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
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