Enterovirus

Enterovirus
Virus classification
Group:	Group IV ((+)ssRNA)
Order:	Picornavirales
Family:	Picornaviridae
Genus:	Enterovirus
Type species
Enterovirus C
Species
Enterovirus A Enterovirus B Enterovirus C Enterovirus D Enterovirus E Enterovirus F Enterovirus G Enterovirus H Enterovirus J Rhinovirus A Rhinovirus B Rhinovirus C

Enteroviruses are a genus of positive-sense single-stranded RNA viruses associated with several human and mammalian diseases. Serologic studies have distinguished 71 human enterovirus serotypes on the basis of antibody neutralization tests. Additional antigenic variants have been defined within several of the serotypes on the basis of reduced or nonreciprocal cross-neutralization between variant strains. On the basis of their pathogenesis in humans and animals, the enteroviruses were originally classified into four groups, polioviruses, Coxsackie A viruses (CA), Coxsackie B viruses (CB), and echoviruses, but it was quickly realized that there were significant overlaps in the biological properties of viruses in the different groups. Enteroviruses isolated more recently are named with a system of consecutive numbers: EV68, EV69, EV70, EV71, etc.^[1]

Enteroviruses affect millions of people worldwide each year, and are often found in the respiratory secretions (e.g., saliva, sputum, or nasal mucus) and stool of an infected person. Historically, poliomyelitis was the most significant disease caused by an enterovirus, poliovirus. There are 64 non-polio enteroviruses that can cause disease in humans: 23 Coxsackie A viruses, 6 Coxsackie B viruses, 28 echoviruses, and 5 other enteroviruses.^[2] Poliovirus, as well as coxsackie and echovirus are spread through the fecal-oral route. Infection can result in a wide variety of symptoms ranging from mild respiratory illness (common cold), hand, foot and mouth disease, acute hemorrhagic conjunctivitis, aseptic meningitis, myocarditis, severe neonatal sepsis-like disease, and acute flaccid paralysis.^[2]

Species and genetics

Maximum likelihood phylogenetic trees of enterovirus species A, B, C, D and rhinovirus A, B, C isolates from Latin America. The 5'UTR region is much more affected by recombination events than the VP4/VP2 coding sequence.^[3]

Enteroviruses are members of the picornavirus family, a large and diverse group of small RNA viruses characterized by a single positive-strand genomic RNA. All enteroviruses contain a genome of approximately 7,500 bases and are known to have a high mutation rate due to low-fidelity replication and frequent recombination.^[4] After infection of the host cell, the genome is translated in a cap-independent manner into a single polyprotein, which is subsequently processed by virus-encoded proteases into the structural capsid proteins and the nonstructural proteins, which are mainly involved in the replication of the virus.^[5]

The enterovirus genus includes the following twelve species:^[6]

• Enterovirus A (formerly Human enterovirus A)
• Enterovirus B (formerly Human enterovirus B)
• Enterovirus C (formerly Human enterovirus C)
• Enterovirus D (formerly Human enterovirus D)
• Enterovirus E (formerly Bovine enterovirus group A)
• Enterovirus F (formerly Bovine enterovirus group B)
• Enterovirus G (formerly Porcine enterovirus B)
• Enterovirus H (formerly Simian enterovirus A)
• Enterovirus J

Within these twelve species are the serotypes:

• Coxsackievirus

  serotypes CV-A2, CV-A3, CV-A4, CV-A5, CV-A6, CV-A7, CV-A8, CV-A10, CV-A12, CV-A14 & CV-A16 found under the species: Enterovirus A.

  serotypes CV-B1, CV-B2, CV-B3, CV-B4, CV-B5, CV-B6 & CV-A9 found under the species: Enterovirus B.

  serotypes CV-A1, CV-A11, CV-A13, CV-A17, CV-A19, CV-A20, CV-A21, CV-A22 & CV-A24 found under the species: Enterovirus C.

• Echovirus

  serotypes E-1, E-2, E-3, E-4, E-5, E-6, E-7, E-9, E-11, E-12, E-13, E-14, E-15, E-16, E-17, E-18, E-19, E-20, E-21, E-24, E-25,
                    E-26, E-27, E-29, E-30, E-31, E-32, & E-33 found under the species: Enterovirus B.

• Enterovirus

  types EV-A71, EV-A76, EV-A89, EV-A90, EV-A91, EV-A92, EV-A114, EV-A119, SV19, SV43, SV46 & BA13 found under the species: Enterovirus A.

  types EV-B69, EV-B73, EV-B74, EV-B75, EV-B77, EV-B78, EV-B79, EV-B80, EV-B81, EV-B82, EV-B83, EV-B84, EV-B85, EV-B86, EV-B87, EV-B88,
                    EV-B93, EV-B97, EV-B98, EV-B100, EV-B101, EV-B106, EV-B107, EV-B110 & SA5 found under the species: Enterovirus B.

  types EV-C95, EV-C96, EV-C99, EV-C102, EV-C104, EV-C105, EV-C109, EV-C116, EV-C117 & EV-C118 found under the species: Enterovirus C.

  types EV-D68, EV-D70, EV-D94, EV-D111 & EV-D120 found under the species: Enterovirus D.

  types: EV-H1 found under the species: Enterovirus H.

  types: SV6, EV-J103, EV-J108, EV-J112, EV-J115 and EV-J121 found under the species: Enterovirus J.

• Human rhinovirus

  types HRV-A1, HRV-A2, HRV-A7, HRV-A8, HRV-A9, HRV-A10, HRV-A11, HRV-A12, HRV-A13, HRV-A15, HRV-A16, HRV-A18, HRV-A19, HRV-A20,
                    HRV-A21, HRV-A22, HRV-A23, HRV-A24, HRV-A25, HRV-A28, HRV-A29, HRV-A30, HRV-A31, HRV-A32, HRV-A33, HRV-A34, HRV-A36,
                    HRV-A38, HRV-A39, HRV-A40, HRV-A41, HRV-A43, HRV-A44, HRV-A45, HRV-A46, HRV-A47, HRV-A49, HRV-A50, HRV-A51, HRV-A53,
                    HRV-A54, HRV-A55, HRV-A56, HRV-A57, HRV-A58, HRV-A59, HRV-A60, HRV-A61, HRV-A62, HRV-A63, HRV-A64, HRV-A65, HRV-A66,
                    HRV-A67, HRV-A68, HRV-A71, HRV-A73, HRV-A74, HRV-A75, HRV-A76, HRV-A77, HRV-A78, HRV-A80, HRV-A81, HRV-A82, HRV-A85,
                    HRV-A88, HRV-A89, HRV-A90, HRV-A94, HRV-A95, HRV-A96, HRV-A98, HRV-A100, HRV-A101, HRV-A102 & HRV-A103 found under the species: Rhinovirus A.

  types HRV-B3, HRV-B4, HRV-B5, HRV-B6, HRV-B14, HRV-B17, HRV-B26, HRV-B27, HRV-B35, HRV-B37, HRV-B42, HRV-B48, HRV-B52, HRV-B69, HRV-B70,
                    HRV-B72, HRV-B79, HRV-B83, HRV-B84, HRV-B86, HRV-B91, HRV-B92, HRV-B93, HRV-B97, & HRV-B99 found under the species: Rhinovirus B.

  types HRV-C1, HRV-C2, HRV-C3, HRV-C4, HRV-C5, HRV-C6, HRV-C7, HRV-C8, HRV-C9, HRV-C10, HRV-C11, HRV-C12, HRV-C13, HRV-C14,
                    HRV-C15, HRV-C16, HRV-C17, HRV-C18, HRV-C19, HRV-C20, HRV-C21, HRV-C22, HRV-C23, HRV-C24, HRV-C25, HRV-C26,
                    HRV-C27, HRV-C28, HRV-C29, HRV-C30, HRV-C31, HRV-C32, HRV-C33, HRV-C34, HRV-C35, HRV-C36, HRV-C37, HRV-C38,
                    HRV-C39, HRV-C40, HRV-C41, HRV-C42, HRV-C43, HRV-C44, HRV-C45, HRV-C46, HRV-C47, HRV-C48, HRV-C49, HRV-C50 & HRV-C51 found under the species: Rhinovirus C.

• Poliovirus

  serotypes PV-1, PV-2, & PV-3 found under the species: Enterovirus C.^[7]

Coxsackie and echovirus

Coxsackie viruses are a non-phylogenetic group.^[8] Coxsackie A viruses are mainly associated with human hand, foot and mouth disease. Coxsackie B viruses can cause signs and symptoms, similar to a "cold," but these viruses also can lead to more serious diseases, including myocarditis (inflammation of the heart); pericarditis (inflammation of the sac lining the heart); meningitis (inflammation of the membranes that line the brain and spinal cord); and pancreatitis (inflammation of the pancreas).

Echoviruses are a cause of many of the nonspecific viral infections. It is mainly found in the intestine, and can cause nervous disorders. The usual symptoms of Coxsackie and echovirus are fever, mild rash, and mild upper respiratory tract (URT) illness.

Enterovirus 68

EV-D68 first was identified in California in 1962. Compared with other enteroviruses, it has been rarely reported in the U.S. in the past 40 years. Most people who get infected are infants, children and teens. EV-D68 usually causes mild to severe respiratory illness; however, the full spectrum of EV-D68 illness is not well-defined. Most start with common cold symptoms of runny nose and cough. Some, but not all, may also have fever. For more severe cases, difficulty breathing, wheezing or problems catching your breath may occur. As of October 4, 2014, there has been one death in New Jersey directly linked to EV-D68,^[9] as well as one death in Rhode Island^[10] attributed to a combination of EV-D68 and sepsis caused by an infection of staphylococcus aureus.^[11][12]

Enterovirus 71

Enterovirus 71 (EV-71) is notable as one of the major causative agents for hand, foot and mouth disease (HFMD), and is sometimes associated with severe central nervous system diseases.^[13] EV71 was first isolated and characterized from cases of neurological disease in California in 1969.^[14][15] To date, little is known about the molecular mechanisms of host response to EV71 infection, but increases in the level of mRNAs encoding chemokines, proteins involved in protein degradation, complement proteins, and proapoptotis proteins have been implicated.^[16]

Poliovirus

There are three serotypes of poliovirus, PV1, PV2, and PV3; each with a slightly different capsid protein. Capsid proteins define cellular receptor specificity and virus antigenicity. PV1 is the most common form encountered in nature; however, all three forms are extremely infectious.^[17] Poliovirus can affect the spinal cord and cause poliomyelitis.

Polioviruses were formerly classified as a species belonging to the genus Enterovirus in the family Picornaviridae. The Poliovirus species has been eliminated from the genus Enterovirus. The following serotypes, Human poliovirus 1, Human poliovirus 2, and Human poliovirus 3, were assigned to the species Human enterovirus C, in the genus Enterovirus in the family Picornaviridae. The type species of the genus Enterovirus was changed from Poliovirus to Human enterovirus C. This has been ratified in April 2008.^[18] The 39th Executive Committee (EC39) of the International Committee on Taxonomy of Viruses (ICTV) met in Canada during June 2007 with new taxonomic proposals.^[19]
Two of the proposals with three changes were:

• Code 2005.261V.04: To remove the following species Poliovirus from the existing genus Enterovirus in the family Picornaviridae.
• Code 2005.262V.04: To assign the viruses; PV-1, PV-2, PV-3 to the existing species Human enterovirus C in the genus Enterovirus in the family Picornaviridae.^[20]
• Code 2005.263V.04: To change the type species Poliovirus from the existing genus Enterovirus in the family Picornaviridae to the type species Human enterovirus C.^[21]

Proposals approved at the (EC39) meeting of 2007, were sent to members of ICTV via email for ratification and have become official taxonomy. There have been a total of 215 taxonomic proposals, which have been approved and ratified since the 8th ICTV Report of 2005.^[22]
The ratification process was performed by email. The proposals were sent electronically via email on March 18, 2008 to ICTV members with a request to vote on whether to ratify the taxonomic proposals, with a 1-month deadline. The following are two of the taxonomic proposals with three changes that were ratified by ICTV members in April 2008:
Picornaviruses

• 2005.261V.04: To remove the following species from the existing genus Enterovirus in the family Picornaviridae: Poliovirus.
  (Note: Poliovirus hereby loses its status as a virus species).
• 2005.262V.04: To assign the following viruses to the species Human enterovirus C in the existing genus Enterovirus in the family Picornaviridae: Human poliovirus 1, Human poliovirus 2, Human poliovirus 3. (This is not strictly necessary as a taxonomic proposal because it concerns entities below the species level, but it is left in to clarify this reorganization of the Picornaviridae).
• 2005.263V.04: To change the type species of the genus Enterovirus in the family Picornaviridae, from Poliovirus to Human enterovirus C.^[18]

The ICTVdb, International Committee on Taxonomy of Viruses data base, based on the ICTV Master Species List, 8th Report, June 2005 is obsolete.^[6]

Diseases caused by enterovirus infection

• Poliomyelitis primarily via the fecal-oral route
• Polio-like syndrome found in children who tested positive for enterovirus 68.^[23][24]
• Nonspecific febrile illness is the most common presentation of enterovirus infection. Other than fever, symptoms include muscle pain, sore throat, gastrointestinal distress/abdominal discomfort, and headache. In newborns the picture may be that of sepsis however, and can be severe and life-threatening.
• Enteroviruses are by far the most common causes of aseptic meningitis in children. In the United States, enteroviruses are responsible for 30,000 to 50,000 meningitis hospitalizations per year as a result of 30 million to 50 million infections.^[2]
• Bornholm disease or epidemic pleurodynia is characterized by severe paroxysmal pain in the chest and abdomen, along with fever, and sometimes nausea, headache, and emesis.
• Pericarditis and/or myocarditis are typically caused by enteroviruses; symptoms consist of fever with dyspnea and chest pain. Arrhythmias, heart failure, and myocardial infarction have also been reported.
• Acute hemorrhagic conjunctivitis can be caused by enteroviruses.
• Herpangina is caused by Coxsackie A virus, and causes a vesicular rash in the oral cavity and on the pharynx, along with high fever, sore throat, malaise, and often dysphagia, loss of appetite, back pain, and headache. It is also self-limiting, with symptoms typically ending in 3–4 days.
• Hand, foot and mouth disease is a childhood illness most commonly caused by infection by Coxsackie A virus or EV71.
• Encephalitis is rare manifestation of enterovirus infection; when it occurs, the most frequent enterovirus found to be causing it is echovirus 9.
• A 2007 study suggested that acute respiratory or gastrointestinal infections associated with enterovirus may be a factor in chronic fatigue syndrome.^[25]
• Diabetes mellitus type 1 It has been proposed that type 1 diabetes is a virus-triggered autoimmune response in which the immune system attacks virus-infected cells along with the insulin-producing beta cells in the pancreas.^[26] A team working at University of Tampere, Finland has identified a type of enterovirus that has a possible link to type 1 diabetes (which is an autoimmune disease).^[27][28]

Treatment

Treatment for enteroviral infection is mainly supportive. In cases of pleurodynia, treatment consists of analgesics to relieve the severe pain that occurs in patients with the disease; in some severe cases, opiates may be needed. Treatment for aseptic meningitis caused by enteroviruses is also mainly symptomatic. In patients with enteroviral carditis, treatment consists of the prevention and treatment of complications, such as arrhythmias, pericardial effusion, and cardiac failure. Other treatments that have been investigated for enteroviral carditis include intravenous immunoglobulin.^[29]

References

1. Oberste MS, Maher K, Kilpatrick DR, Pallansch MA (1999). "Molecular Evolution of the Human Enteroviruses: Correlation of Serotype with VP1 Sequence and Application to Picornavirus Classification". J. Virol. 73 (3): 1941–8. PMC 104435. PMID 9971773.
2. "Non-Polio Enterovirus Infections". CDC. 8 September 2014. Retrieved 9 September 2014.
3. Josefina Garcia; et al. (2013). "Human rhinoviruses and enteroviruses in influenza-like illness in Latin America". Virol J. 10: 305. doi:10.1186/1743-422x-10-305. PMC 3854537. PMID 24119298.
4. Li L, He Y, Yang H; et al. (2005). "Genetic Characteristics of Human Enterovirus 71 and Coxsackievirus A16 Circulating from 1999 to 2004 in Shenzhen, People's Republic of China". J. Clin. Microbiol. 43 (8): 3835–9. doi:10.1128/JCM.43.8.3835-3839.2005. PMC 1233905. PMID 16081920.
5. Merkle I, van Ooij MJ, van Kuppeveld FJ; et al. (2002). "Biological Significance of a Human Enterovirus B-Specific RNA Element in the 3′ Nontranslated Region". J. Virol. 76 (19): 9900–9. doi:10.1128/JVI.76.19.9900-9909.2002. PMC 136489. PMID 12208967.
7. "ICTV Master Species List 2009 - v10 (9th Report) - Master Species Lists - Master Species Lists - ICTV Collaboration". Talk.ictvonline.org. 2009-10-21. Retrieved 2016-04-14.
8. Santti, Juhana; Heli Harvala; Leena Kinnunen; Timo Hyypia (2000). "Molecular epidemiology and evolution of coxsackievirus A9" (PDF). Journal of General Virology 81 (Pt 5): 1361–1372. PMID 10769080. Retrieved 2009-08-09.
9. Mohney, Gillian (4 October 2014). "Medical Examiner Finds NJ Preschooler Died Due to Enterovirus 68". ABCNews. Retrieved 6 October 2014.
10. WDRI.com
11. "The facts about enterovirus D68". Childrensmn.org. Children's Hospitals and Clinics of Minnesota.
12. Malone, Scott (1 October 2014). "Rhode Island child with Enterovirus dies after infection: officials". Reuters. Retrieved 6 October 2014.
13. Lin TY, Chu C, Chiu CH (2002). "Lactoferrin inhibits enterovirus 71 infection of human embryonal rhabdomyosarcoma cells in vitro". J. Infect. Dis. 186 (8): 1161–4. doi:10.1086/343809. PMID 12355368.
14. Wang JR, Tuan YC, Tsai HP, Yan JJ, Liu CC, Su IJ (2002). "Change of Major Genotype of Enterovirus 71 in Outbreaks of Hand-Foot-and-Mouth Disease in Taiwan between 1998 and 2000". J. Clin. Microbiol. 40 (1): 10–5. doi:10.1128/JCM.40.1.10-15.2002. PMC 120096. PMID 11773085.
15. Laboratory Investigation of a Suspected Enterovirus 71 Outbreak
16. Shih SR, Stollar V, Lin JY, Chang SC, Chen GW, Li ML (2004). "Identification of genes involved in the host response to enterovirus 71 infection". J. Neurovirol. 10 (5): 293–304. doi:10.1080/13550280490499551. PMID 15385252.
17. Paul JR (1971). A History of Poliomyelitis. (Yale studies in the history of science and medicine). New Haven, Conn: Yale University Press. ISBN 0-300-01324-8.
18. Carstens, E. B.; Ball, L. A. (July 2009). "Ratification vote on taxonomic proposals to the International Committee on Taxonomy of Viruses (2008)" (PDF). Archives of Virology (Springer Wien) 154 (7): 1181–1188. doi:10.1007/s00705-009-0400-2. ISSN 1432-8798. PMID 19495937.
19. "ICTV Newsletter #6 2008" (PDF). ICTV. February 2008. p. 1.
20. "2005.261-262V.04.Polio.pdf - Vertebrate (through 2014) - Approved Proposals since the 8th Report - ICTV Collaboration". Talk.ictvonline.org. 2008-03-05. Retrieved 2016-04-14.
21. "2005.263V.04.TypeSpEntero.pdf - Vertebrate (through 2014) - Approved Proposals since the 8th Report - ICTV Collaboration". Talk.ictvonline.org. 2008-03-05. Retrieved 2016-04-14.
22. "ICTV Newsletter #7 2009" (PDF). ICTV. October 2009. p. 1.
23. Seroka, Rachel (23 February 2014). "Mysterious polio-like illness found in 5 California children". American Academy of Neurology. Retrieved 24 February 2014.
24. "Mysterious Polio-Like Illness Found in California Children". Voice of America. February 24, 2014. Retrieved 24 February 2014.
25. Chia, JKS; et al. (2007). "Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach". J Clin Pathol 61: 43–48. doi:10.1136/jcp.2007.050054.
26. Fairweather, D; Rose, NR (2002). "Type 1 diabetes: virus infection or autoimmune disease?". Nat. Immunol. 3: 338–340. doi:10.1038/ni0402-338. PMID 11919574.
27. "Finnish team makes diabetes vaccine breakthrough | Yle Uutiset". Yle.fi. Retrieved 2016-04-14.
28. Laitinen, OH; et al. (2014). "Coxsackievirus B1 is associated with induction of β-cell autoimmunity that portends type 1 diabetes". Diabetes 63: 446–455. doi:10.2337/db13-0619. PMID 23974921.
29. Schwartz, R.A. "Enteroviruses Treatment & Management". Medscape.

External links

• ICTV International Committee on Taxonomy of Viruses (official site)
• Home of Picornaviruses (latest updates of species, serotypes, & proposed changes)
• alertnet.org, FACTBOX-Q&A on hand, foot and mouth disease
• Enterovirus on ExPASy Proteomics from the Swiss Institute of Bioinformatics