Coxsackie B virus

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Coxsackie B4 virus.

Coxsackie B (also written coxsackievirus B) is a group of six types of enterovirus belonging to the Picornaviridae family. They cause symptoms ranging from gastrointestinal distress to aseptic meningitis, pericarditis and myocarditis. Like other enteroviruses, Coxsackie B viruses have a tropism for muscle cells and have been linked to myalgic encephalomyelitis and chronic fatigue syndrome, as well as Type 1 Diabetes.

Symptoms[edit | edit source]

Symptoms of infection with viruses in the Coxsackie B grouping include fever, headache, sore throat, gastrointestinal distress, extreme fatigue as well as chest and muscle pain. It can also lead to spasms in arms and legs.

Types[edit | edit source]

Coxsackie B1[edit | edit source]

Coxsackie B2[edit | edit source]

Coxsackie B3[edit | edit source]

Coxsackie B3 is found in 20-25% of patients with cardiomyopathy and myocarditis.[1][2][3][4]

Coxsackie B4[edit | edit source]

Coxsackievirus B4 has a cell tropism for natural killer cells and pancreatic islet cells.[citation needed]

Coxsackie B5[edit | edit source]

Coxcackie B6[edit | edit source]

Immune system[edit | edit source]

In a mouse model of myocarditis, Coxsackievirus infection was found to upregulate Toll-like receptor 4 on mast cells and macrophages immediately following infection. It also increased numbers of mast cells.[5]

The induction of interferon signaling and the induction of apoptosis are required for normal control of a Coxsackie B3 infection. Coxsackievirus B3 cleaves Mitochondrial Antiviral Signaling (MAVS) protein and Toll/IL-1 receptor domain-containing adaptor inducing interferon-beta TRIF to inhibit type I interferon induction and evade host immunity.[6] Conversely, upregulation of MAVS inhibits Coxsackie B3 by increasing type-1 interferon production.[7]

Mitochondria[edit | edit source]

Coxsackievirus B3 cleaves Mitochondrial Antiviral Signaling (MAVS) protein to inhibit type I interferon induction.[8] Conversely, upregulation of MAVS inhibits coxsackie B3 by increasing type-1 interferon production.[9]

Exercise[edit | edit source]

Several studies of a mouse model of Coxsackie B3 myocarditis have found that exercise increases the virulence of the infection and results in poorer outcomes.[10][11][12][13][14] These studies compare two groups of mice, both infected with CVB3, one that is exercised and the other, sedentary. They found:

  • Exercised mice died of congestive heart failure (the majority while swimming) and had 530X the amount of virus.[13]
  • Exercised mice had increased viral titers, mortality and fiber necrosis.[11]
  • Exercised mice had higher viremia and virus in the hearts and no circulating interferon; non-exercised mice had detectable interferon activity, higher levels of neutralizing antibodies[14]
  • Exercised mice died at much higher rates (52% v. 0 sedentary mice), but not if they were immunosuppressed.[10]
  • Increased T cytotoxic, T suppressor, and T cytotoxic, suppressor/T helper cell ratio, and myocardial inflammatory and necrotic lesions with exercise at 48 hours after infection. "Failure to restrict physical activity in the acute phase of this infection may well contribute to the progression of the disease."[12]

Chronic infection[edit | edit source]

Some researchers believe that Coxsackie B enteroviruses establish a persistent, intracellular, non-cytolytic infection, that is an infection that does not involve the destruction of infected cells. Non-cytolytic infection is difficult to measure in the serum as viral particles remain in the cell walls of tissues.

The molecular mechanisms of non-cytolytic infection were examined in a small study comparing Coxsackie B2 virus cultured in vitro to RNA extracted via muscle biopsy from eight patients with a chronic fatigue syndrome diagnosis. All patients had symptoms of muscle fatiguability. Four of these samples tested positive for enteroviral RNA. In all four patients with enteroviral-specific RNA, the enteroviral RNA had equal amounts of positive sense and negative sense RNA. By contrast, CVB2 virus in culture produced positive sense RNA at a ratio of 100:1. An equal ratio of positive to negative sense RNA would inhibit the translation of virus-specific gene products, explaining the failure to attract a response from the host immune system, and my account for how CVB2 could establish a persistent infection in these four patients.[15]

Models of persistent infection of the heart[16] and brain[17] have also been studied in mice and in thyroid carcinoma.

In human disease[edit | edit source]

Viruses in the Coxsackie B family progress to myocarditis or pericarditis, which can result in permanent heart damage or death. Coxsackie B virus infection may also induce aseptic meningitis. As a group, they are the most common cause of unexpected sudden death, and may account for up to 50% of such cases.[18]

Myalgic Encephalomyelitis[edit | edit source]

Some researchers and clinicians postulate that ME is caused by an enteroviral infection. Several studies have patients with ME to have persistently elevated levels of Coxsackie B IgM or IgG antibodies, circulating immune complexes containing viral antigen, or presence of enterovirus by PCR or culture, all indicating the possible presence of a persistent infection.[19][20] Others studies failed to find a difference in rates of positivity between patients and controls. Differences in study outcomes may be due to the criteria used to define study cohorts as well as the techniques used.

Blood testing[edit | edit source]

Elevated Coxsackie B antibodies have been found in patients in at least two ME outbreaks.[21][22] In a retrospective cohort study[23] by Melvin Ramsay and Elizabeth Dowsett, 31% of the patients were found to have elevated enteroviral IgM antibody levels. Sixteen of these patients were retested annually over three years and all showed persistently elevated Coxsackie B neutralizing antibody levels and intermittently positive enteroviral IgM, suggesting a persistent infection was present.

Similarly, a study of of 76 patients with postviral fatigue syndrome (PVFS) found that 76% had detectible IgM responses to enteroviruses. 22% had positive cultures (compared to 7% controls) and VP1 antigen was detected in 51%, all pointing to a chronic infection in many post-viral patients.[24] However, a larger study in Scotland of 243 PVFS patients and matched controls found no difference in IgM and IgG positivity between patients and controls.[25]

PCR[edit | edit source]

In a study of serum samples from 100 CFS patients and 100 healthy controls, 42% of patients were positive for Coxsackie B sequences by PCR, compared to only 9% of the comparison group.[26]

Also using PCR, a study of 236 patients by John Chia found enteroviral RNA in 48% of patients as compared to 8% of controls.To date, Chia reports finding enteroviral RNA in 35% of 518 patients.[20]

Muscle biopsy[edit | edit source]

Several muscle biopsy studies have also found the presence of Coxsackie B RNA sequences in CFS patients as compared to controls. A study of 60 post-viral fatigue syndrome patients found 53% had enteroviral RNA in muscle compared to 15% of controls.[27] However, a follow-up study comparing CFS patients to patients with other neuromuscular disorders failed to find a statistically significant difference.[28]

Type 1 diabetes[edit | edit source]

Several studies have suggested a relationship between Coxsackie B4 and the onset of Type 1 diabetes.[29][30][31]

A study of patients with Type 1 Diabetes found that Coxsackie B4 was found to infect the β cells in the pancreatic islets of the pancreas and cause inflammation mediated by natural killer cells.[32]

Testing[edit | edit source]

In the United States, ARUP Laboratories offers a serum microneutralization assay that is designed to measure the concentration of serum antibodies to six serotypes of the virus; B1 through B6. This specific assay has been shown to be sensitive for detection of chronic infections in ME patients. A persistent fourfold or greater rise in antibody titer is often found in these patients, which is not often found in healthy controls.

A complement fixation assay for Coxsackie B serotypes is available in the United States from LabCorp and Quest Diagnostics, however this specific type of assay has not been found to be sensitive for the chronic infections found in ME patients.

Antivirals[edit | edit source]

There are no approved vaccines or antivirals for Coxsackie viruses, and there have been no human trials. Preliminary research (often in animal models or in vitro) have been shown various compounds to have potential antiviral effects, but it is not known whether these compounds have or could be used to create interventions with any clinical benefit in humans.

John Chia reported that treatment with Interferon and Ribavirin on patients with B3 or B5 appeared to show some benefit, but patients relapsed after discontinuation of treatment. One patient with B4 experienced moderate improvement on Pleconaril but also relapsed.[20]

Selenium deficiency increases the virulence of Coxsackie B3 infections in a mouse model.[33] In mouse models, Ampligen was found to be protective of Coxsackie B3-induced myocarditis.[34]

Compounds with antiviral activity
Serotype Pharmaceuticals Herbs Supplements Other Protective factors Risk factors
B1 Fluoxetine[35] ursolic acid, Bupleurum kaoi Glycine max *
B2 Fluoxetine[35] simalikalactone D * *
B3 Ampligen[36],Fluoxetine[35], Interferon[37], ribvarin, arbidol[38], amiloride, itraconazole, oseltamivir, bosentan[39], valsartan,[39] olmesartan, lovastatin, mycophenolate, arsenic trioxide shuang huang lian, garlic, curcumin, baicalein, Paris polyphylla, raoulic acid, Dodonaea viscosa, Spatholobus suberectus, Terminalia chebula, Trichosanthes root, Rhodiola rosea, emodin[40], Astragalus membranaceus[41], acemannan, Sophora flavescens, Isatis tinctoria, cinnamaldehyde, Rheum palmatum, Oroxylin A[42] chlorogenic acid, fatty acid synthase inhibitors selenium[43] exercise[11][12][13][14]
B4 Fluoxetine[44], oseltamivir, arbidol[45] Yakammaoto[46], raoulic acid[47], emodin[48] Epimedium, Azadirachta indica (Neem)[49] Dihydroquercetin(Taxifolin)[50] DHEA, 5-androstenediol
B5 arbidol[51] Spatholobus suberectus, Terminalia chebula, Epimedium, hyaluronic acid[52] sodium selenite chlorogenic acid, clinoptilolite
B6 * Azadirachta indica * *
Note: Many of the elements in this table were reproduced from a post on Phoenix Rising. See that post for full citations and/or help us fully cite this table.

See also[edit | edit source]

References[edit | edit source]

  1. ↑ Jin O, Sole MJ, Butany JW, Chia WK, McLaughlin PR, et al. (1990) Detection of enterovirus RNA in myocardial biopsies from patients with myocarditis and cardiomyopathy using gene amplification by polymerase chain reaction. Circulation 82: 8–16.
  2. ↑ Bowles NE, Richardson PJ, Olsen EG, Archard LC (1986) Detection of Coxsackie-B-virus-specific RNA sequences in myocardial biopsy samples from patients with myocarditis and dilated cardiomyopathy. Lancet 1: 1120–1123.
  3. ↑ Martin AB, Webber S, Fricker FJ, Jaffe R, Demmler G, et al. (1994) Acute myocarditis. Rapid diagnosis by PCR in children. Circulation 90: 330–339.
  4. ↑ Jin O, Sole MJ, Butany JW, Chia WK, McLaughlin PR, et al. (1990) Detection of enterovirus RNA in myocardial biopsies from patients with myocarditis and cardiomyopathy using gene amplification by polymerase chain reaction. Circulation 82: 8–16.
  5. ↑ http://www.ncbi.nlm.nih.gov/pubmed/15386590
  6. ↑ Mukherjee, A (March 2011). "The coxsackievirus B 3C protease cleaves MAVS and TRIF to attenuate host type I interferon and apoptotic signaling". PLoS Pathology. 7.
  7. ↑ http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3546859/
  8. ↑ Mukherjee, A (March 2011). "The coxsackievirus B 3C protease cleaves MAVS and TRIF to attenuate host type I interferon and apoptotic signaling". PLoS Pathology. 7.
  9. ↑ http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3546859/
  10. ↑ 10.0 10.1 Cabinian AE, Kiel RJ, Smith F, Ho KL, Khatib R, Reyes MR. Modification of exercise-aggravated coxsackie virus B3 murine myocarditis by T-lymphocyte suppression in an inbred model. J. Lab. Clin. Med. 1990; 115: 454– 62.
  11. ↑ 11.0 11.1 11.2 Kiel RJ, Smith FE, Chason J, Khatib R, Reyes MD. Coxsackie B3 myocarditis in C3H/HeJ mice: Description of an inbred model and the effect of exercise on the virulence. Eur. J. Epidemiol. 1989; 5: 248– 67.
  12. ↑ 12.0 12.1 12.2 Ilbäck, NG (June 1989). "Exercise in coxsackie B3 myocarditis: Effects on heart lymphocyte subpopulations and the inflammatory reaction". American Heart Journal. 117: 1298–302.
  13. ↑ 13.0 13.1 13.2 Gatmaitan, Bienvenido (June 1, 1970). "Augmentation of the Virulence of Murine Coxsackie Virus B-3 Myocardiopathy by Exercise". Journal of Experimental Medicine. 131: 1121.
  14. ↑ 14.0 14.1 14.2 Reyes, MP (February 1976). "Interferon and neutralizing antibody in sera of exercised mice with coxsackievirus B-3 myocarditis". Proceedings of the Society for Experimental Biology and Medicine. 151: 333–8.
  15. ↑ Cunningham, Louise (1990). "Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA". Journal of General Virology. 71: 1399–1402.
  16. ↑ Chapman N.M., Kim K.S. (2008) Persistent Coxsackievirus Infection: Enterovirus Persistence in Chronic Myocarditis and Dilated Cardiomyopathy. In: Tracy S., Oberste M.S., Drescher K.M. (eds) Group B Coxsackieviruses. Current Topics in Microbiology and Immunology, vol 323. Springer, Berlin, Heidelberg
  17. ↑ Feuer, Ralph (September 2009). "Viral Persistence and Chronic Immunopathology in the Adult Central Nervous System following Coxsackievirus Infection during the Neonatal Period". Journal of Virology. 83: 9356–9369.
  18. ↑ "Coxsackie B virus". Wikipedia. Cite has empty unknown parameter: |dead-url= (help)
  19. ↑ Landay, AL (September 1991). "Chronic fatigue syndrome: clinical condition associated with immune activation". Lancet.
  20. ↑ 20.0 20.1 20.2 Chia, John (November 2005). "The role of enterovirus in chronic fatigue syndrome". Journal of Clinical Pathology.
  21. ↑ Fegan, KG; Behan, PO; Bell, EJ (June 1, 1983), "Myalgic encephalomyelitis — report of an epidemic", J R Coll Gen Pract, 33 (251): 335–337, PMID 6310104
  22. ↑ Calder, BD; Warnock, PJ (January 1984), "Coxsackie B infection in a Scottish general practice", Jrnl Royal Coll Gen Pract, 34 (258): 15–19, PMID 6319691
  23. ↑ Dowsett, EG; Ramsay, AM; McCartney, RA; Bell, EJ (July 1, 1990), "Myalgic encephalomyelitis--a persistent enteroviral infection?", Postgraduate Medical Journal, 66 (777): 526–530, doi:10.1136/pgmj.66.777.526, PMID 2170962
  24. ↑ Yousef, G.E. (January 1988). "CHRONIC ENTEROVIRUS INFECTION IN PATIENTS WITH POSTVIRAL FATIGUE SYNDROME". The Lancet.
  25. ↑ Miller, N A (1991). "Antibody to Coxsackie B virus in diagnosing postviral fatigue syndrome". The British Medical Journal.
  26. ↑ Nairn, C (August 1995). "Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients". Journal of Medical Virology.
  27. ↑ Gow, JW. "Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome". British Medical Journal.
  28. ↑ Gow, JW (1994). "Studies on enterovirus in patients with chronic fatigue syndrome". https://www.ncbi.nlm.nih.gov/pubmed/8148439/. External link in |journal= (help)
  29. ↑ http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1587352/
  30. ↑ http://link.springer.com/article/10.1007%2Fs00125-003-1297-z
  31. ↑ http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057729
  32. ↑ http://www.pnas.org/content/104/12/5115.full
  33. ↑ http://jn.nutrition.org/content/130/2/485S.full
  34. ↑ Padalko, E (January 2004). "The interferon inducer ampligen [poly(I)-poly(C12U)] markedly protects mice against coxsackie B3 virus-induced myocarditis". Antimicrobial Agents and Chemotherapy. 48: 267–74.
  35. ↑ 35.0 35.1 35.2 Zuo, J (September 2012). "Fluoxetine is a potent inhibitor of coxsackievirus replication". Antimicrobial Agents and Chemotherapy. 56: 4838–44.
  36. ↑ http://www.ncbi.nlm.nih.gov/pubmed/14693549
  37. ↑ http://www.ncbi.nlm.nih.gov/pubmed/1328433
  38. ↑ Shi, L (2007). "Antiviral activity of arbidol against influenza A virus, respiratory syncytial virus, rhinovirus, coxsackie virus and adenovirus in vitro and in vivo". Archives of Virology. 152: 1447–55.
  39. ↑ 39.0 39.1 Funke, Carsten (2010). "Antiviral effect of Bosentan and Valsartan during coxsackievirus B3 infection of human endothelial cells" (PDF). Journal of General Virology. 91: 1959–1970. line feed character in |title= at position 50 (help)
  40. ↑ Zhang, HM (February 2016). "Emodin inhibits coxsackievirus B3 replication via multiple signalling cascades leading to suppression of translation". Biochem J.
  41. ↑ http://www.ncbi.nlm.nih.gov/pubmed/8580483
  42. ↑ Kwon, Bo-Eun (May 19, 2016). "Antiviral Activity of Oroxylin A against Coxsackievirus B3 Alleviates Virus-Induced Acute Pancreatic Damage in Mice". PLoS One.
  43. ↑ Levander, Orville A. (February 1, 2000), "The Selenium-Coxsackievirus Connection: Chronicle of a Collaboration", The Journal of Nutrition, 130 (2): 485–488S, ISSN 0022-3166, PMID 10721935, retrieved November 9, 2016
  44. ↑ Alidjinou, AK (April 2015). "Persistent infection of human pancreatic cells with Coxsackievirus B4 is cured by fluoxetine". Antiviral Research. 116: 51–4.
  45. ↑ Zhang, S (May 2017). "Umifenovir effectively inhibits IL-10 dependent persistent Coxsackie B4 virus infection". Antiviral Research. 141: 165–173.
  46. ↑ https://www.ncbi.nlm.nih.gov/pubmed/24361333
  47. ↑ Choi, HJ (January 2009). "Antiviral activity of raoulic acid from Raoulia australis against Picornaviruses". Phytomedicine.
  48. ↑ Liu, Zhao (October 2013). "In Vitro and in Vivo Studies of the Inhibitory Effects of Emodin Isolated from Polygonum cuspidatum on Coxsakievirus B-4". Molecules.
  49. ↑ Badam, L (1999). "'In vitro' antiviral activity of neem (Azadirachta indica. A. Juss) leaf extract against group B coxsackieviruses". J Commun Dis.
  50. ↑ http://www.ncbi.nlm.nih.gov/pubmed/27145597
  51. ↑ Zhong, Qiong (April 2009). "Antiviral activity of Arbidol against Coxsackie virus B5 in vitro and in vivo". Archives of Virology. 154.
  52. ↑ http://www.ncbi.nlm.nih.gov/pubmed/21439070

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enterovirus A genus of RNA viruses which typically enter the body through the respiratory or gastrointestinal systems and sometimes spread to the central nervous system or other parts of the body, causing neurological, cardiac, and other damage. Since the first reports of myalgic encephalomyelitis (ME), enteroviruses have been suspected as a cause of ME. Enteroviruses have also been implicated as the cause of Type I diabetes, congestive heart failure, and other conditions. Enteroviruses include poliovirus, coxsackieviruses, and many others. New enteroviruses and new strains of existing enteroviruses are continuously being discovered. (Learn more: viralzone.expasy.org)

mouse model The use of special strains of mice to study a human disease or condition, and how to prevent and treat it

β β / Β. Greek letter beta (a symbol used in science), equivalent to "b".

mitochondria Important parts of the biological cell, with each mitochondrion encased within a mitochondrial membrane. Mitochondria are best known for their role in energy production, earning them the nickname "the powerhouse of the cell". Mitochondria also participate in the detection of threats and the response to these threats. One of the responses to threats orchestrated by mitochondria is apoptosis, a cell suicide program used by cells when the threat can not be eliminated.

antibodies Antibody/immunoglobulin refers to any of a large number of specific proteins produced by B cells that act against an antigen in an immune response.

antibodies Antibody/immunoglobulin refers to any of a large number of specific proteins produced by B cells that act against an antigen in an immune response.

serum The clear yellowish fluid that remains from blood plasma after clotting factors have been removed by clot formation. (Blood plasma is simply blood that has had its blood cells removed.)

enterovirus A genus of RNA viruses which typically enter the body through the respiratory or gastrointestinal systems and sometimes spread to the central nervous system or other parts of the body, causing neurological, cardiac, and other damage. Since the first reports of myalgic encephalomyelitis (ME), enteroviruses have been suspected as a cause of ME. Enteroviruses have also been implicated as the cause of Type I diabetes, congestive heart failure, and other conditions. Enteroviruses include poliovirus, coxsackieviruses, and many others. New enteroviruses and new strains of existing enteroviruses are continuously being discovered. (Learn more: viralzone.expasy.org)

myalgic encephalomyelitis (M.E.) - A disease often marked by neurological symptoms, but fatigue is sometimes a symptom as well. Some diagnostic criteria distinguish it from chronic fatigue syndrome, while other diagnostic criteria consider it to be a synonym for chronic fatigue syndrome. A defining characteristic of ME is post-exertional malaise (PEM), or post-exertional neuroimmune exhaustion (PENE), which is a notable exacerbation of symptoms brought on by small exertions. PEM can last for days or weeks. Symptoms can include cognitive impairments, muscle pain (myalgia), trouble remaining upright (orthostatic intolerance), sleep abnormalities, and gastro-intestinal impairments, among others. An estimated 25% of those suffering from ME are housebound or bedbound. The World Health Organization (WHO) classifies ME as a neurological disease.

enterovirus A genus of RNA viruses which typically enter the body through the respiratory or gastrointestinal systems and sometimes spread to the central nervous system or other parts of the body, causing neurological, cardiac, and other damage. Since the first reports of myalgic encephalomyelitis (ME), enteroviruses have been suspected as a cause of ME. Enteroviruses have also been implicated as the cause of Type I diabetes, congestive heart failure, and other conditions. Enteroviruses include poliovirus, coxsackieviruses, and many others. New enteroviruses and new strains of existing enteroviruses are continuously being discovered. (Learn more: viralzone.expasy.org)

antibodies Antibody/immunoglobulin refers to any of a large number of specific proteins produced by B cells that act against an antigen in an immune response.

β β / Β. Greek letter beta (a symbol used in science), equivalent to "b".

assay 1. (verb) analysis (as of an ore or drug) to determine the presence, absence, or quantity of one or more components. 2. (noun) In biochemistry, any laboratory protocol used to test a sample for one or more qualities.

mouse model The use of special strains of mice to study a human disease or condition, and how to prevent and treat it

enterovirus A genus of RNA viruses which typically enter the body through the respiratory or gastrointestinal systems and sometimes spread to the central nervous system or other parts of the body, causing neurological, cardiac, and other damage. Since the first reports of myalgic encephalomyelitis (ME), enteroviruses have been suspected as a cause of ME. Enteroviruses have also been implicated as the cause of Type I diabetes, congestive heart failure, and other conditions. Enteroviruses include poliovirus, coxsackieviruses, and many others. New enteroviruses and new strains of existing enteroviruses are continuously being discovered. (Learn more: viralzone.expasy.org)

BMJ The BMJ (previously the British Medical Journal) is a weekly peer-reviewed medical journal.

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