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Coxsackieviruses are a few related enteroviruses that belong to the ''
Picornaviridae Picornaviruses are a group of related nonenveloped RNA viruses which infect vertebrates including fish, mammals, and birds. They are viruses that represent a large family of small, positive-sense, single-stranded RNA viruses with a 30  ...
'' family of
nonenveloped A viral envelope is the outermost layer of many types of viruses. It protects the genetic material in their life cycle when traveling between host cells. Not all viruses have envelopes. Numerous human pathogenic viruses in circulation are encas ...
, linear,
positive-sense single-stranded RNA virus Positive-strand RNA viruses (+ssRNA viruses) are a group of related viruses that have positive-sense, single-stranded genomes made of ribonucleic acid. The positive-sense genome can act as messenger RNA (mRNA) and can be directly translated i ...
es, as well as its genus ''Enterovirus'', which also includes
poliovirus A poliovirus, the causative agent of polio (also known as poliomyelitis), is a serotype of the species '' Enterovirus C'', in the family of '' Picornaviridae''. There are three poliovirus serotypes: types 1, 2, and 3. Poliovirus is composed of ...
and
echovirus Echovirus is a polyphyletic group of viruses associated with enteric disease in humans. The name is derived from "enteric cytopathic human orphan virus". These viruses were originally not associated with disease, but many have since been identif ...
. Enteroviruses are among the most common and important human pathogens, and ordinarily its members are transmitted by the
fecal–oral route The fecal–oral route (also called the oral–fecal route or orofecal route) describes a particular route of transmission of a disease wherein pathogens in fecal particles pass from one person to the mouth of another person. Main causes of fec ...
. Coxsackieviruses share many characteristics with poliovirus. With control of poliovirus infections in much of the world, more attention has been focused on understanding the nonpolio enteroviruses such as coxsackievirus. Coxsackieviruses are among the leading causes of aseptic meningitis (the other usual suspects being echovirus and
mumps virus The mumps virus (MuV) is the virus that causes mumps. MuV contains a single-stranded, negative-sense genome made of ribonucleic acid (RNA). Its genome is about 15,000 nucleotides in length and contains seven genes that encode nine proteins. The ...
). The entry of coxsackievirus into cells, especially endothelial cells, is mediated by coxsackievirus and adenovirus receptor.


Groups

Coxsackieviruses are divided into group A and group B viruses based on early observations of their pathogenicity in neonatal mice. Group A coxsackieviruses were noted to cause a
flaccid paralysis Flaccid paralysis is a neurological condition characterized by weakness or paralysis and reduced muscle tone without other obvious cause (e.g., trauma). This abnormal condition may be caused by disease or by trauma affecting the nerves associa ...
(which was caused by generalized myositis) while group B coxsackieviruses were noted to cause a spastic paralysis (due to focal muscle injury and degeneration of neuronal tissue). At least 23
serotypes A serotype or serovar is a distinct variation within a species of bacteria or virus or among immune cells of different individuals. These microorganisms, viruses, or cells are classified together based on their surface antigens, allowing the ep ...
(1–22, 24) of group A and six serotypes (1–6) of group B are recognized.


Group A

In general, group A coxsackieviruses tend to infect the skin and mucous membranes, causing
herpangina Herpangina, also called mouth blisters, is a painful mouth infection caused by coxsackieviruses. Usually, herpangina is produced by one particular strain of coxsackie virus A (and the term "herpangina virus" refers to coxsackievirus A), but it can ...
; acute hemorrhagic
conjunctivitis Conjunctivitis, also known as pink eye, is inflammation of the outermost layer of the white part of the eye and the inner surface of the eyelid. It makes the eye appear pink or reddish. Pain, burning, scratchiness, or itchiness may occur. Th ...
; and hand, foot, and mouth disease. Both group A and group B coxsackieviruses can cause nonspecific febrile illnesses, rashes, upper respiratory tract disease, and aseptic meningitis. The basic reproduction number (R0) for Coxsackievirus A16 (Cox A16) was estimated to a median of 2.50 with an interquartile range of 1.96 to 3.67.


Group B

Group B coxsackieviruses tend to infect the heart, pleura, pancreas, and liver, causing pleurodynia,
myocarditis Myocarditis, also known as inflammatory cardiomyopathy, is an acquired cardiomyopathy due to inflammation of the heart muscle. Symptoms can include shortness of breath, chest pain, decreased ability to exercise, and an irregular heartbeat. Th ...
, pericarditis, and
hepatitis Hepatitis is inflammation of the liver tissue. Some people or animals with hepatitis have no symptoms, whereas others develop yellow discoloration of the skin and whites of the eyes ( jaundice), poor appetite, vomiting, tiredness, abdominal ...
(inflammation of the liver not related to the hepatotropic viruses). Coxsackie B infection of the heart can lead to
pericardial effusion A pericardial effusion is an abnormal accumulation of fluid in the pericardial cavity. The pericardium is a two-part membrane surrounding the heart: the outer fibrous connective membrane and an inner two-layered serous membrane. The two layers of t ...
. The development of
insulin-dependent diabetes Type 1 diabetes (T1D), formerly known as juvenile diabetes, is an autoimmune disease that originates when cells that make insulin (beta cells) are destroyed by the immune system. Insulin is a hormone required for the cells to use blood sugar f ...
has recently been associated with recent enteroviral infection, particularly coxsackievirus B
pancreatitis Pancreatitis is a condition characterized by inflammation of the pancreas. The pancreas is a large organ behind the stomach that produces digestive enzymes and a number of hormones. There are two main types: acute pancreatitis, and chronic p ...
. This relationship is currently being studied further. Sjögren syndrome is also being studied in connection with coxsackievirus, .


Taxonomy

There were 29 species of coxsackieviruses until 1999, when two of them were abolished and the rest merged into other species.ICTV 7th Report van Regenmortel, M.H.V., Fauquet, C.M., Bishop, D.H.L., Carstens, E.B., Estes, M.K., Lemon, S.M., Maniloff, J., Mayo, M.A., McGeoch, D.J., Pringle, C.R. and Wickner, R.B. (2000). Virus taxonomy. Seventh report of the International Committee on Taxonomy of Viruses. Academic Press, San Diego. 1162 pp. https://talk.ictvonline.org/ictv/proposals/ICTV%207th%20Report.pdf


History

The coxsackieviruses were discovered in 1948–49 by Gilbert Dalldorf, a scientist working at the New York State Department of Health in
Albany, New York Albany ( ) is the capital of the U.S. state of New York, also the seat and largest city of Albany County. Albany is on the west bank of the Hudson River, about south of its confluence with the Mohawk River, and about north of New York Cit ...
. Dalldorf, in collaboration with Grace Sickles, had been searching for a cure for
poliomyelitis Poliomyelitis, commonly shortened to polio, is an infectious disease caused by the poliovirus. Approximately 70% of cases are asymptomatic; mild symptoms which can occur include sore throat and fever; in a proportion of cases more severe sym ...
. Earlier work Dalldorf had done in monkeys suggested that fluid collected from a nonpolio virus preparation could protect against the crippling effects of polio. Using newborn mice as a vehicle, Dalldorf attempted to isolate such protective viruses from the feces of polio patients. In carrying out these experiments, he discovered viruses that often mimicked mild or nonparalytic polio. The virus family he discovered was eventually given the name Coxsackie, from
Coxsackie, New York Coxsackie ( ) is a town in Greene County, New York, United States. The population in the 2020 census was 8,382, a decrease from the 2010 census. The name of the town is said to be derived from a Native American term, but it has various transla ...
, a small town on the Hudson River where Dalldorf had obtained the first fecal specimens. Dalldorf also collaborated with Gifford on many early papers. The coxsackieviruses subsequently were found to cause a variety of infections, including epidemic pleurodynia ( Bornholm disease), and were subdivided into groups A and B based on their pathology in newborn mice. (Coxsackie A virus causes paralysis and death of the mice, with extensive skeletal muscle necrosis; Coxsackie B causes less severe infection in the mice, but with damage to more organ systems, such as heart, brain, liver, pancreas, and skeletal muscles.) The use of suckling mice was not Dalldorf's idea but was brought to his attention in a paper written by Danish scientists Orskov and Andersen in 1947, who were using such mice to study a mouse virus. The discovery of the coxsackieviruses stimulated many virologists to use this system, and ultimately resulted in the isolation of a large number of so-called "enteric" viruses from the gastrointestinal tract that were unrelated to poliovirus, and some of which were oncogenic (cancer-causing). The discovery of the coxsackieviruses yielded further evidence that viruses can sometimes interfere with each other's growth and replication within a host animal. Other researchers found this interference can be mediated by a substance produced by the host animal, a protein now known as
interferon Interferons (IFNs, ) are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten th ...
. Interferon has since become prominent in the treatment of a variety of cancers and infectious diseases. In 2007, an outbreak of coxsackievirus occurred in eastern China. It has been reported that 22 children died. More than 800 people were affected, with 200 children hospitalized.. Cavatak, a wild-type Coxsackievirus A21, is being used in human clinical trials as an
oncolytic virus An oncolytic virus is a virus that preferentially infects and kills cancer cells. As the infected cancer cells are destroyed by oncolysis, they release new infectious virus particles or virions to help destroy the remaining tumour. Oncolytic viru ...
.


References


External links


3D macromolecular structures of Coxsackieviruses from the EM Data Bank(EMDB)
{{Diseases of the skin and appendages by morphology Enteroviruses Unaccepted virus taxa Polyphyletic groups