thumb | right | alt=Coxsackie B4 virus seen with an immunoelectron microscope. | Coxsackie B4 virus seen with an immunoelectron microscope.

Coxsackie B4 virus are enteroviruses that belong to the Picornaviridae family. These viruses can be found worldwide. They are positive-sense, single-stranded, non-enveloped RNA viruses with icosahedral geometry. Coxsackieviruses have two groups, A and B, each associated with different diseases. Coxsackievirus group A is known for causing hand-foot-and-mouth diseases while Group B, which contains six serotypes, can cause a varying range of symptoms like gastrointestinal distress myocarditis. Coxsackievirus B4 has a cell tropism for natural killer cells and pancreatic islet cells. Infection can lead to beta cell apoptosis which increases the risk of insulitis.

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.

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), which can be found on heart muscle cells as well as epithelial and endothelial cells, 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.

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

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.

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.

Coxsackie B4 virus and type 1 diabetes

One theory proposes that type 1 diabetes is a virus-triggered autoimmune response in which the immune system attacks virus-infected cells along with the beta cells in the pancreas, but to date there is no stringent evidence to support this hypothesis in humans.

A 2004 systematic review analyzing a possible association between coxsackievirus B infection and type 1 diabetes was inconclusive. A 2011 systematic review and meta-analysis showed an association between enterovirus infections and type 1 diabetes, but in contrast, other studies have shown that rather than triggering an autoimmune process, enterovirus infections, as coxsackievirus B, could protect against onset and development of type 1 diabetes.

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 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.

See also

  • Coxsackie B virus

References

  • "Conquering Diabetes: A Strategic Plan for the 21st Century". National Institutes of Health.