Coxsackie B4 virus: Difference between revisions
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An absolute deficiency of insulin renders the person a [[Diabetes mellitus type 1|type 1 diabetic]]. Of the several viruses in the [[coxsackievirus|Coxsackie]] family, many of them seem to evoke this response, as do several other agents. A genetic predisposition appears to be important, such that individuals with [[human leukocyte antigen]] types DR3 and DR4 predominate in the affected population. |
An absolute deficiency of insulin renders the person a [[Diabetes mellitus type 1|type 1 diabetic]]. Of the several viruses in the [[coxsackievirus|Coxsackie]] family, many of them seem to evoke this response, as do several other agents. A genetic predisposition appears to be important, such that individuals with [[human leukocyte antigen]] types DR3 and DR4 predominate in the affected population. |
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==Viral Structure and Genome== |
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Coxsackievirus B4 is one of the six serotypes found in Group B and is a positive sense, single-stranded, non-enveloped RNA virus. Its genome is linear and is 7,293 nucleotides in length with both a 5’ and 3’ untranslated region and encodes its own 3’ poly-A tail. The 5’ untranslated region contains an internal ribosomal entry site (Type I IRES). Covalently bonded to the 5’ UTR is the viral protein VPg which aids in viral entry and replication. 2A and 3C are viral proteinases which aid in the cleavage of the polyprotein encoded for by the genome. 3D is the RNA-dependent RNA polymerase (RdRP). 2B, 2C, and 3A are core viral proteins. The genome also codes for 4 capsid proteins, VP4, VP1, VP2, and VP3 that form an icosahedral capsid for the viral particles that is about 30 nm. VP1-VP3 are responsible for the outer surface of the virion, while VP4 is imbedded within the capsid.<ref name="RiabiHarrath2014">{{cite journal|last1=Riabi|first1=Samira|last2=Harrath|first2=Rafik|last3=Gaaloul|first3=Imed|last4=Bouslama|first4=Lamjed|last5=Nasri|first5=Dorsaf|last6=Aouni|first6=Mahjoub|last7=Pillet|first7=Sylvie|last8=Pozzetto|first8=Bruno|title=Study of Coxsackie B viruses interactions with Coxsackie Adenovirus receptor and Decay-Accelerating Factor using Human CaCo-2 cell line|journal=Journal of Biomedical Science|volume=21|issue=1|year=2014|pages=50|issn=1423-0127|doi=10.1186/1423-0127-21-50}}</ref> |
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Altogether, the polyprotein encoded for by the coxsackievirus genome is almost 2,200 amino acids in length, and is eventually cleaved by the 2A and 3C proteinases as well as by host cell proteinases. |
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As Coxsackievirus B4, and all other members of the picornavirus family, are non-enveloped, they are notably resilient to disinfectants, solvents, low pH levels (i.e. stomach acid), low temperatures, and 70% alcohol. |
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==Viral Replication== |
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===ATTACHMENT, ENTRY, AND UNCOATING=== |
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The capsid of Coxsackie viruses have a distinguishable depression around the fivefold axis, termed the “canyon.” The canyon is thought to help with viral attachment through the interaction with cell surface molecules. (Riabi, 2014) When VP1 binds to the Coxsackie-Adenovirus receptor (CAR) found on epithelial and endothelial cells,<ref name="Dorner2005">{{cite journal|last1=Dorner|first1=A. A.|title=Coxsackievirus-adenovirus receptor (CAR) is essential for early embryonic cardiac development|journal=Journal of Cell Science|volume=118|issue=15|year=2005|pages=3509–3521|issn=0021-9533|doi=10.1242/jcs.02476}}</ref> a conformational change causes the host cell receptors to form a pore in the plasma membrane through which the VPg-linked viral genome could enter the cell. <ref name="RiabiHarrath2014">{{cite journal|last1=Riabi|first1=Samira|last2=Harrath|first2=Rafik|last3=Gaaloul|first3=Imed|last4=Bouslama|first4=Lamjed|last5=Nasri|first5=Dorsaf|last6=Aouni|first6=Mahjoub|last7=Pillet|first7=Sylvie|last8=Pozzetto|first8=Bruno|title=Study of Coxsackie B viruses interactions with Coxsackie Adenovirus receptor and Decay-Accelerating Factor using Human CaCo-2 cell line|journal=Journal of Biomedical Science|volume=21|issue=1|year=2014|pages=50|issn=1423-0127|doi=10.1186/1423-0127-21-50}}</ref> Uncoating is unnecessary as it leaves the capsid at the plasma membrane and the genome is simply injected into the cytoplasm. |
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===REPLICATION=== |
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For positive sense, single-stranded RNA viruses, translation occurs before transcription. Upon entry of the genome into the cytoplasm of the host cell, the IRES in the 5’ UTR recruits ribosomal subunits (cap-independent mechanism) which starts the translation process. Once the polypeptide is completely translated, viral proteinases 2A and 3C, as well as cellular proteinases, cleave the polyprotein into individual proteins that will help continue the viral replication process.<ref>R. Hunt. (April 2010). “Virology-Chapter Ten picornaviruses-Part one Enteroviruses and General Features of Picornaviruses.” Micobiology and Immunology. University of South Carolina School of Medicine.</ref> |
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As soon as viral proteins have been translated and cleaved, negative sense transcripts of the viral genome are made to serve as a template for more positive-sense viral genome transcripts (which also serves as mRNA which can also be translated into more viral proteins). The viral genome encodes for a poly-A tail, which can be recognized by cellular initiation factors and ribosomal subunits which kick starts the transcription process to make the negative-sense strand, forming a double-stranded RNA intermediate<ref>Espasy. [http://viralzone.expasy.org/all_by_protein/97.html/“Enteroviruses”] SIB Swiss Institute of Bioinformatics. </ref> |
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Upon transcription of the negative sense RNA, it needs to get primed in order to start making more positive sense RNA genome. The VPg protein that is covalently linked to the 5’ end of the RNA genome has 2 U’s attached to it. The purpose of these U’s is to modify the VPg protein which serves as a protein primer which the viral RdRP can recognize and start forming more genome from the negative-sense.<ref>Espasy. [http://viralzone.expasy.org/all_by_protein/97.html/“Enteroviruses”] SIB Swiss Institute of Bioinformatics. </ref> |
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The viral protein 2C brings positive sense RNA genomes to the endoplasmic reticulum where assembly and maturation will occur.<ref>R. Hunt. (April 2010). “Virology-Chapter Ten picornaviruses-Part one Enteroviruses and General Features of Picornaviruses.” Micobiology and Immunology. University of South Carolina School of Medicine.</ref> |
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While all of this is occurring, viral proteinases are working to turn off host cell protein synthesis by cleaving the eIF-4 initiation factor. This process accomplishes the inhibition of ribosomes binding to host cell mRNAs. This effectively shuts down cap-dependent translation in the host cell.<ref>R. Hunt. (April 2010). “Virology-Chapter Ten picornaviruses-Part one Enteroviruses and General Features of Picornaviruses.” Micobiology and Immunology. University of South Carolina School of Medicine.</ref> |
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===ASSEMBLY, MATURATION, AND EGRESS=== |
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Once viral genome and viral proteins reach high enough concentrations within the host cell, structural proteins must assemble. The final step in maturation of the virus is when VP0, a precursor protein, is cleaved into VP2 and VP4. Viral capsid proteins come together to form pentamers, 12 of which come together to form an empty capsid, or procapsid (Expasy, Hunt, 2010). |
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As mentioned before, the viral protein 2C brings CB4 viral genome to the endoplasmic reticulum where vesicle formation begins. The ER membrane moves to surround the genome and proteins, at which point the procapsid attaches to the exterior of the vesicle and encapsidates the genome and proteins. It is at this point that VP0 gets cleaved by a cellular proteinase and the virus finally becomes fully mature and infectious. Since CB4 is a non-enveloped virus, it accomplishes egress through cytolysis, breaking through the plasma membrane in order to move on to infect other cells in the host (Hunt, 2010) |
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==Symptoms== |
==Symptoms== |
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Revision as of 23:55, 25 November 2014
| Coxsackievirus B4 virus | |
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| Coxsackie B4 virus | |
| Virus classification | |
| Group: | Group IV ((+)ssRNA)
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| Family: | |
| Genus: | |
| Species: | |
| Subtype | |
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Coxsackie B4 virus | |
Coxsackie B4 virus is a serotype of Enterovirus B, genus Enterovirus, which can trigger an autoimmune reaction which results in destruction of the insulin-producing beta cells of the pancreas, which is one of several different etiologies of diabetes mellitus.
An absolute deficiency of insulin renders the person a type 1 diabetic. Of the several viruses in the Coxsackie family, many of them seem to evoke this response, as do several other agents. A genetic predisposition appears to be important, such that individuals with human leukocyte antigen types DR3 and DR4 predominate in the affected population.
Viral Structure and Genome
Coxsackievirus B4 is one of the six serotypes found in Group B and is a positive sense, single-stranded, non-enveloped RNA virus. Its genome is linear and is 7,293 nucleotides in length with both a 5’ and 3’ untranslated region and encodes its own 3’ poly-A tail. The 5’ untranslated region contains an internal ribosomal entry site (Type I IRES). Covalently bonded to the 5’ UTR is the viral protein VPg which aids in viral entry and replication. 2A and 3C are viral proteinases which aid in the cleavage of the polyprotein encoded for by the genome. 3D is the RNA-dependent RNA polymerase (RdRP). 2B, 2C, and 3A are core viral proteins. The genome also codes for 4 capsid proteins, VP4, VP1, VP2, and VP3 that form an icosahedral capsid for the viral particles that is about 30 nm. VP1-VP3 are responsible for the outer surface of the virion, while VP4 is imbedded within the capsid.[1] Altogether, the polyprotein encoded for by the coxsackievirus genome is almost 2,200 amino acids in length, and is eventually cleaved by the 2A and 3C proteinases as well as by host cell proteinases.
As Coxsackievirus B4, and all other members of the picornavirus family, are non-enveloped, they are notably resilient to disinfectants, solvents, low pH levels (i.e. stomach acid), low temperatures, and 70% alcohol.
Viral Replication
ATTACHMENT, ENTRY, AND UNCOATING
The capsid of Coxsackie viruses have a distinguishable depression around the fivefold axis, termed the “canyon.” The canyon is thought to help with viral attachment through the interaction with cell surface molecules. (Riabi, 2014) When VP1 binds to the Coxsackie-Adenovirus receptor (CAR) found on epithelial and endothelial cells,[2] a conformational change causes the host cell receptors to form a pore in the plasma membrane through which the VPg-linked viral genome could enter the cell. [1] Uncoating is unnecessary as it leaves the capsid at the plasma membrane and the genome is simply injected into the cytoplasm.
REPLICATION
For positive sense, single-stranded RNA viruses, translation occurs before transcription. Upon entry of the genome into the cytoplasm of the host cell, the IRES in the 5’ UTR recruits ribosomal subunits (cap-independent mechanism) which starts the translation process. Once the polypeptide is completely translated, viral proteinases 2A and 3C, as well as cellular proteinases, cleave the polyprotein into individual proteins that will help continue the viral replication process.[3]
As soon as viral proteins have been translated and cleaved, negative sense transcripts of the viral genome are made to serve as a template for more positive-sense viral genome transcripts (which also serves as mRNA which can also be translated into more viral proteins). The viral genome encodes for a poly-A tail, which can be recognized by cellular initiation factors and ribosomal subunits which kick starts the transcription process to make the negative-sense strand, forming a double-stranded RNA intermediate[4]
Upon transcription of the negative sense RNA, it needs to get primed in order to start making more positive sense RNA genome. The VPg protein that is covalently linked to the 5’ end of the RNA genome has 2 U’s attached to it. The purpose of these U’s is to modify the VPg protein which serves as a protein primer which the viral RdRP can recognize and start forming more genome from the negative-sense.[5]
The viral protein 2C brings positive sense RNA genomes to the endoplasmic reticulum where assembly and maturation will occur.[6]
While all of this is occurring, viral proteinases are working to turn off host cell protein synthesis by cleaving the eIF-4 initiation factor. This process accomplishes the inhibition of ribosomes binding to host cell mRNAs. This effectively shuts down cap-dependent translation in the host cell.[7]
ASSEMBLY, MATURATION, AND EGRESS
Once viral genome and viral proteins reach high enough concentrations within the host cell, structural proteins must assemble. The final step in maturation of the virus is when VP0, a precursor protein, is cleaved into VP2 and VP4. Viral capsid proteins come together to form pentamers, 12 of which come together to form an empty capsid, or procapsid (Expasy, Hunt, 2010). As mentioned before, the viral protein 2C brings CB4 viral genome to the endoplasmic reticulum where vesicle formation begins. The ER membrane moves to surround the genome and proteins, at which point the procapsid attaches to the exterior of the vesicle and encapsidates the genome and proteins. It is at this point that VP0 gets cleaved by a cellular proteinase and the virus finally becomes fully mature and infectious. Since CB4 is a non-enveloped virus, it accomplishes egress through cytolysis, breaking through the plasma membrane in order to move on to infect other cells in the host (Hunt, 2010)
Symptoms
Coxsackie B 1-4 viruses are typically the most severe and fatal neonatal diseases. Common symptoms can include myocarditis, meningoencephalitis, and hepatitis. Other less severe symptoms can include pneumonia, Gastrointestinal symptoms, pancreatitis, and seizures. Patients with Coxsackie B4 virus have seemed to have herpangina, tonsillitis, and pharyngitis.[8]
CB4 virus has caused transplacental infections in mice. Infection in the first couple weeks of gestation has been shown to be harmful for dams as well as the fetus, causing reduced litter sizes, abortion, or stillbirth. Pups that were born from dams infected on days 4 and 17 of gestation had significantly (p < 0.05) greater pancreatic abnormalities leading to symptoms similar to diabetes.[9]
Coxsackie B4 Virus and Diabetes Mellitus
In 1973, Gamble, Taylor, and Cumming published a study that explored the relationship between the incidence of coxsackie B viruses and diabetes mellitus. The study explored the amounts of coxsackie B virus types 1-5 neutralizing antibodies of 162 insulin-independent diabetes patient serum specimens compared with 319 control serum specimens. The data showed that 70% of the insulin-independent diabetes specimens were positive for coxsackie B4 virus, whereas, 58% of the controls had neutralizing antibodies, a p-value less than 0.01. In children less than 10 there were 45% of diabetics presenting with coxsackie B4 neutralizing antibodies and 48% of the control group presented with coxsackie B4 neutralizing antibodies. If there were a correlation between coxsackie B4 virus it would have been expected to see diabetes in these patients. The researchers concluded that the viral infection may not be directly causing diabetes, but rather over time causing damage to the pancreatic cells.[10] Later studies showed that coxsackie B4 virus is able to persistently infect beta-cells in the pancreas that would lead to a loss in function.[11]
In 2013, Caterina Bason and others were able to identify the relationship between CB4 and diabetes mellitus. Type-1 diabetes is an autoimmune disease that results in the lack of production of insulin by beta cells in the islets of Langerhans in the human pancreas. Enteroviruses to which coxsackie B4 belong, have a tropism for the islet-cells in the human pancreas.[12] Coxsackie B4 virus shares a sequence homology with a Type 1 diabetes mellitus peptide. The peptide homology is found on the VP1 protein, which is a glycoprotein for the coxsackie B4 virus. In the early stages of the infection macrophages and T-cells will secrete cytokines and granzymes to contribute to beta-cell apoptosis and increasing the risk of insulitis.[13]
Transmission to Neonates
Enteroviruses commonly infect neonates and infants younger than 12 months. Coxsackie b viruses are usually spread to infants through perinatal transmission. However, more severe severe cases of coxsackie B viruses are spread through transplacental transmission. Common symptoms of neonatal coxsackie B virus infection in children include meningitis and/or encephalitis. Coxsackie B4 virus is able to infect the brain and spinal cord and cause inflammation.[8]
Diagnosis
Infection due to Coxsackie B viruses can be determined by measuring the amount of neutralizing antibodies in the blood, PCR, and through microscopic detection. It is difficult to diagnose CBV based on the symptoms.[14]
See also
External links
References
- ^ a b Riabi, Samira; Harrath, Rafik; Gaaloul, Imed; Bouslama, Lamjed; Nasri, Dorsaf; Aouni, Mahjoub; Pillet, Sylvie; Pozzetto, Bruno (2014). "Study of Coxsackie B viruses interactions with Coxsackie Adenovirus receptor and Decay-Accelerating Factor using Human CaCo-2 cell line". Journal of Biomedical Science. 21 (1): 50. doi:10.1186/1423-0127-21-50. ISSN 1423-0127.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Dorner, A. A. (2005). "Coxsackievirus-adenovirus receptor (CAR) is essential for early embryonic cardiac development". Journal of Cell Science. 118 (15): 3509–3521. doi:10.1242/jcs.02476. ISSN 0021-9533.
- ^ R. Hunt. (April 2010). “Virology-Chapter Ten picornaviruses-Part one Enteroviruses and General Features of Picornaviruses.” Micobiology and Immunology. University of South Carolina School of Medicine.
- ^ Espasy. [1] SIB Swiss Institute of Bioinformatics.
- ^ Espasy. [2] SIB Swiss Institute of Bioinformatics.
- ^ R. Hunt. (April 2010). “Virology-Chapter Ten picornaviruses-Part one Enteroviruses and General Features of Picornaviruses.” Micobiology and Immunology. University of South Carolina School of Medicine.
- ^ R. Hunt. (April 2010). “Virology-Chapter Ten picornaviruses-Part one Enteroviruses and General Features of Picornaviruses.” Micobiology and Immunology. University of South Carolina School of Medicine.
- ^ a b Del Bigio, Marc; Herath, Jayantha; Menticoglou, Savas; Schneider, Carol; Hunt, Jennifer (2011). "Antenatal and Postnatal Diagnosis of Coxsackie B4 Infection: Case Series". American Journal of Perinatology Reports. 02 (01): 001–006. doi:10.1055/s-0031-1296027. ISSN 2157-6998.
- ^ Bopegamage, Shubhada; Precechtelova, Jana; Marosova, Lenka; Stipalova, Darina; Sojka, Martin; Borsanyiova, Maria; Gomolcak, Pavol; Berakova, Katarina; Galama, Jochem M. D. (2012). "Outcome of challenge with coxsackievirus B4 in young mice after maternal infection with the same virus during gestation". FEMS Immunology & Medical Microbiology. 64 (2): 184–190. doi:10.1111/j.1574-695X.2011.00886.x. ISSN 0928-8244.
{{cite journal}}: Unknown parameter|displayauthors=ignored (|display-authors=suggested) (help) - ^ Gamble, D.R., Taylor, K.W., and Cumming, H. (November 1973). "Coxsackie Viruses and Diabetes Mellitus." British Medical Journal 4(5887): 260-2. PMCID 1587352
- ^ Dotta, F.; Censini, S.; van Halteren, A. G. S.; Marselli, L.; Masini, M.; Dionisi, S.; Mosca, F.; Boggi, U.; Muda, A. O.; Prato, S. D.; Elliott, J. F.; Covacci, A.; Rappuoli, R.; Roep, B. O.; Marchetti, P. (2007). "Coxsackie B4 virus infection of beta cells and natural killer cell insulitis in recent-onset type 1 diabetic patients". Proceedings of the National Academy of Sciences. 104 (12): 5115–5120. doi:10.1073/pnas.0700442104. ISSN 0027-8424.
- ^ Ylipaasto, P.; Klingel, K.; Lindberg, A. M.; Otonkoski, T.; Kandolf, R.; Hovi, T.; Roivainen, M. (2004). "Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells". Diabetologia. 47 (2): 225–239. doi:10.1007/s00125-003-1297-z. ISSN 0012-186X.
- ^ von Herrath, Matthias G.; Bason, Caterina; Lorini, Renata; Lunardi, Claudio; Dolcino, Marzia; Giannattasio, Alessandro; d’Annunzio, Giuseppe; Rigo, Antonella; Pedemonte, Nicoletta; Corrocher, Roberto; Puccetti, Antonio (2013). "In Type 1 Diabetes a Subset of Anti-Coxsackievirus B4 Antibodies Recognize Autoantigens and Induce Apoptosis of Pancreatic Beta Cells". PLoS ONE. 8 (2): e57729. doi:10.1371/journal.pone.0057729. ISSN 1932-6203.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Shors, T. (2013). Understanding Viruses. (2nd ed.) (pg. 439). Burlington, MA: Jones & Bartlett Learning.