Enteroviruses

Enteroviruses Enteroviruses are a genus of the

picornavirus family which replicate mainly in the gut.

Single stranded naked RNA virus with icosahedral symmetry

Unlike rhinoviruses, they are stable in acid pH

Capsid has 60 copies each of 4 proteins, VP1, VP2, VP3 and VP4 arranged with icosahedral symmetry around a positive sense genome.

At least 71 serotypes are known: divided into 5 groups– Polioviruses -Coxsackie A

viruses– Coxsackie B viruses -Echoviruses– Enteroviruses (more recently, new

enteroviruses subtype have been allocated sequential numbers (68-71))

Enterovirus Particles

Courtesy of Linda M. Stannard, University of Cape Town, S.A.h

  Genera of PicornavirusesEnterovirus

PolioCoxsackie A and B

EchoOther enteroviruses

Diseases of the human (and other) alimentary tract (e.g. polio virus)

Rhinovirus Disease of the nasopharyngeal region (e.g. common cold virus)

Cardiovirus Murine encephalomyocarditis, Theiler's murine encephalomyelitis virus

Aphthovirus Foot and mouth disease in cloven footed animals

Hepatovirus Human hepatitis virus A

Others Drosophila C virus, equine rhinoviruses, cricket paralysis virus

History Poliovirus - first identified in 1909 by inoculation

of specimens into monkeys. The virus was first grown in cell culture in 1949 which became the basis for vaccines.

Coxsackieviruses - In 1948, a new group of agents were identified by inoculation into newborn mice from two children with paralytic disease. These agents were named coxsackieviruses after the town in New York State. Coxsackieviruses A and B were identified on the basis of the histopathological changes they produced in Newborn mice and their capacity to grow in cell cultures.

Echoviruses - were later identified which produced cytopathic changes in cell culture and was nonpathogenic for newborn mice and subhuman primates.

More recently, new enterovirus types have been allocated sequential numbers (68 - 71).

Categories of Enteroviruses

Viral meningitis, rash,ARD4 types(68-71)Other Enteroviruses

Viral meningitis, with orchitis32 typesEchioviruses

Viral meningitis, but no orchitis6 types (B1-B6)Coxsackie B viruses

Viral meningitis plus, rash, ARD, myocarditis, orchitis

23 types ( A1-A22, A24)

Coxsackie A viruses

Asymptomatic infection, viral meningitis, paraalytic disease, poliomyelitis

3 typesPolioviruses

Clinical DiseasesSerotypesVirus

Properties of Enteroviruses CPE in cell cultures Monkey Human cell Pathology in Group Virus types kidney culture newborn mice Major disease associations Poliovirus 3 types + + - Paralytic poliomyelitis, aseptic (1 - 3) meningitis, febrile illness. Coxsackie 23 types - or E - or E + Aseptic meningitis, herpangina, group A (A1-22, A24) febrile illness, conjunctivitis (A24), hand, foot and mouth disease. Coxsackie 6 types + + + Aseptic meningitis, severe neonatal group B (B1-6) disease, myopericarditis, Bornholm disease, encephalitis, febrile illness. Echovirus 31 types + E - Aseptic meningitis, rash, febrile (1-9, 11-27 illness, conjunctivitis, severe 29-33) generalized neonatal disease. Enterovirus 5 types + + - Polio-like illness, aseptic (68-72) meningitis, hand, foot and mouth (E71), epidemic conjunctivitis (E70) hepatitis A (E72)

Properties of enterovirusesProperty Enteroviruses

Size (nm)Capsid form PolypeptideRNA typeRNA molecular weightAcidOptimal temperature for growth(oC)Density in caesium chloride (g/m)

22-30

Icosahedral VP1, VP2, VP3, VP4SS-PS2000,000-2600,000Stable*371.34*

Transmission

Fecal – oral route: poor hygiene, dirty diapers( especially in day-care settings)

Ingestion via contaminated food and water

Contact with infected hands Inhalation of infectious aerosols

Pathogenesis of enterovirus infection

Rhino,echo,

coxsackie,polio

Replication in oropharynx

Primary viremia

Target Tissue Secondary viremia

Skin Muscle Brain Meninges Liver

Echo

Coxsackie

A

Echo

Coxsackie

A, B

Polio

Coxsackie

Echo

Polio

Coxsackie

Echo

Coxsackie

Poliovirus

3 serotypes of poliovirus (1, 2, and3) but no common antigen.

Have identical physical properties but only share 36-52% nucleotide homology.

Humans are the only susceptible hosts. Polioviruses are distributed globally. Before the

availability of immunization, almost 100% of the population in developing countries before the age of 5.

The availability of immunization and the poliovirus eradication campaign has eradicated poliovirus in most regions of the world except in the Indian Subcontinent and Africa.

Poliovirus is on course of being eradicated worldwide by the end of 2000 or 2001.

Pathogenesis

The incubation period is usually 7 - 14 days. Following ingestion, the virus multiplies in the

oropharyngeal and intestinal mucosa.

The lymphatic system, in particular the tonsils and the Peyer's patches of the ileum are invaded and the virus enters the blood resulting in a transient viraemia.

In a minority of cases, the virus may involve the CNS following dissemination.

Clinical Manifestations

There are 3 possible outcomes of infection:

– Subclinical infection (90 - 95%) - inapparent subclinical infection account for the vast majority of poliovirus infections.

– Abortive infection (4 - 8%) - a minor influenza-like illness occurs, recovery occurs within a few days and the diagnosis can only be made by the laboratory. The minor illness may be accompanied by aseptic meningitis

– Major illness (1 - 2%) - the major illness may present 2 - 3 days following the minor illness or without any preceding minor illness. Signs of aseptic meningitis are common. Involvement of the anterior horn cells lead to flaccid paralysis. Involvement of the medulla may lead to respiratory paralysis and death.

Victims of paralytic polio

Child with polio sequelae 

Laboratory Diagnosis Virus Isolation

– Mainstay of diagnosis of poliovirus infection– poliovirus can be readily isolated from

throat swabs, faeces, and rectal swabs. It is rarely isolated from the CSF

– Can be readily grown and identified in cell culture

– Requires molecular techniques to differentiate between the wild type and the vaccine type.

Serology– Very rarely used for diagnosis since cell

culture is efficient. Occasionally used for immune status screening for immunocompromised individuals.

Prevention

No specific antiviral therapy is available. However the disease may be prevented through vaccination. There are two vaccines available.

Both oral polio vaccine( OPV live, attenuated ， Sabin, 1957) and inactivated poliovirus vaccine(IPV ， Salk, 1954) are avilable

****IPV is used for adult immunization and Immunocopromised patients

Prevention Intramuscular Poliovirus Vaccine (IPV)

– consists of formalin inactivated virus of all 3 poliovirus serotypes.

– Produces serum antibodies only: does not induce local immunity and thus will not prevent local infection of the gut.

– However, it will prevent paralytic poliomyelitis since viraemia is essential for the pathogenesis of the disease.

Oral Poliovirus Vaccine (OPV)– Consists of live attenuated virus of all 3 serotypes. – Produces local immunity through the induction of an

IgA response as well as systemic immunity.– Rarely causes paralytic poliomyelitis, around 1 in 3

million doses. Most countries use OPV because of its ability to induce

local immunity and also it is much cheaper to produce than IPV.

The normal response rate to OPV is close to 100%.

Current Status of Wild Poliovirus Transmission

Coxsackie Virus

Coxsackieviruses Coxsackieviruses are distinguished from other

enteroviruses by their pathogenicity for infant rather than adult mice. They are divided into 2 groups on the basis of the lesions observed in suckling mice.– Group A viruses produce a diffuse myositis with

acute inflammation and necrosis of fibers of voluntary muscles.

– Group B viruses produce focal areas of degeneration in the brain, necrosis in the skeletal muscles, and inflammatory changes in the dorsal fat pads, the pancreas and occasionally the myocardium.

Each of the 23 group A and 6 group B coxsackieviruses have a type specific antigen.

In addition, all from group B and one from group A (A9) share a group Ag. Cross-reactivities have also been demonstrated between several group A viruses but no common group antigen has been found.

Features of coxsackievirus infection in the labortory

Types Growth in MK Effect in cell culture sucking mice

Coxsackie A virus 1-24 a + ParalysisCoxsackie B virus 1-6 + Spasticity

MK , monkey kidney a Coxsackievirus A23 now classified as echovirus 9

Features of coxsackievirus infection in man

Coxsackievirus A 1-24 Asptic meningitis

Febrile illness Herpangina

Hand-foot-and-mouth disease Coxsackievirus B 1-6

Neonatal disease Myocarditis, hepatitis

Meningitis

Disease Associations Paralytic Disease - most commonly associated with polioviruses but

other enteroviruses may also be responsible, especially enterovirus 71 Meningitis - caused by all groups of enteroviruses, most commonly

seen in children under 5 years of age. Encephalitis - focal or generalized encephalitis may accompany

meningitis. Most patients recover completely with no neurological deficit.

Undifferentiated febrile illness - may be seen with all groups of enteroviruses.

Hand foot mouth disease - usually caused by group A coxsackieviruses although group B coxsackieviruses and other enteroviruses have been caused outbreaks.

Herpangina caused by group A coxsackieviruses. Epidemic Pleurodynia (pain of the side) - normally caused by group B

coxsackieviruses.

Myocarditis - group B coxsackieviruses are the major cause of myocarditis, although it may be caused by other enteroviruses. It may present in neonates as part of neonatal infection and is often fatal. In adults, the disease is rarely fatal.

Respiratory Infections - several enteroviruses are associated with the common cold.

Rubelliform rashes - a rash disease resembling rubella may be seen with several coxsackie A, B, and echoviruses.

Neonatal Infection - some coxsackie B viruses and echoviruses may cause infection in newborn infants. The virus is usually transmitted perinatally during the birth process and symptoms vary from a mild febrile illness to a severe fulminating multisystem disease and death.

Conjunctivitis - associated with several types of enteroviruses, especially Coxsackie A24 and Enterovirus 70 (haemorrhagic conjunctivitis)

Pancreatitis /Diabetes - associated with Coxsackie B virus infection. The extent of the role of the virus in diabetes is unknown.

Exanthems – Rubelliform rashes

Hand-foot-and-mouth disease

Hand-foot-and-mouth

disease: mostly coxackie A

– fever, malaise, sore throat,

vesicles on bucal mucosa,

tongue, hands, feet, buttocks

highly infectious

Herpangina

Herpangina – usually coxackie A acute onset, fever, sore throat,

dysphagi (difficulty in swallowing )

lesions – posterior pharynx

can persist w’s

no gingivitis

ECHO virus

Echoviruses

The first echoviruses were accidentally discovered in human faeces, unassociated with human disease during epidemiological studies of polioviruses. The viruses were named echoviruses (enteric, cytopathic, human, orphan viruses).

These viruses were produced CPE in cell cultures, but did not induce detectable pathological lesions in suckling mice.

Completely , There are 32 echoviruses (types 1-34; echovirus 10 and 28 were found to be other viruses and thus the numbers are unused)

There is no group echovirus Ag but heterotypic cross-reactions occur between a few pairs.

Important Characteristics

Not produce diseases in sucking mice, rabbits, or monkeys;

Cause aseptic meningitis, infantile diarrhea,

Monkey kidney and human embryonated kidney cell culture

Clinical syndromes associated with

echoviruses Main syndromes Aseptic meningitis Paralysis Rash Respiratory disease Other features Pericarditis and myocarditis Neonatal infection

Illness associated with recently identified enteroviruses

Enterovirus 68 Pneumonia and bronchiolitis

Enterovirus 69 Isolated from an ill person in Mexico

Enterovirus 70 Acute hameorrhagic conjunctivitis

Enterovirus 70, 71 Paralysis, meningo-encephalitis

Enterovirus 71 hand-foot-and-mouth disease

Enterovirus 72 Hepatovirus( Hepatitis A)

New Enteroviruses Newly identified picornaviruses that are not

polioviruses are no longer classified separated into the species coxsackie and echovirus because of the ambiguities presented by overlapping host range variations.

4 new enteroviruses have been identified (68 - 72). Enterovirus 70 is the causative agent epidemics of acute haemorrhagic conjunctivitis that swept (move rapidly) through Africa, Asia, India and Europe from 1969 to 1974. The virus is occasionally neurovirulent.

Enterovirus 71 appears to be highly pathogenic and has been associated with epidemics of a variety of acute diseases, including aseptic meningitis, encephalitis, paralytic poliomyelitis-like disease and hand-foot-mouth disease.

Enterovirus 72 was originally assigned to hepatitis A virus, but it had now been assigned to a new family called heptoviruses.

Diseases associated with EnterovirusesSyndrome Polio Cox A Cox B Echo Paralytic disease + + + + Meningitis-encephalitis + + + + Carditis + + + + Neonatal disease - - + + Pleurodynia - - + - Herpangina - + - - Rash disease - + + + Haemorr. conjunctivitis - + - - Respiratory infections + + + + Undifferentiated fever + + + + Diabetes/pancreatitis - - + -

Laboratory Diagnosis Virus Isolation

– Mainstay of diagnosis of enterovirus infection

– Coxsackie B and Echoviruses can be readily grown in cell culture from throat swabs, faeces, and rectal swabs. They can also be isolated from the CSF

– Coxsackie A viruses cannot be easily isolated in cell culture. They can be isolated readily in suckling mice but this is not offered by most diagnostic laboratories because of practical considerations. Molecular techniques may provide a better alternative.

Serology– Very rarely used for diagnosis since cell

culture is efficient.– Neutralization tests or EIAs are used but are

very cumbersome and thus not offered by most diagnostic laboratories

Cytopathic Effect

(Virology Laboratory, New-Yale Haven Hospital)

Management and Prevention

There is no specific antiviral therapy available against enteroviruses other than polio.

Some authorities use IVIG in the treatment of neonatal infections or severe infections in immunocompromised individuals. However, the efficacy is uncertain.

HNIG have been to prevent outbreaks of neonatal infection with good results.

There is no vaccine available mainly because of the multiplicity of serotypes. There is little interest in developing a vaccine except against enterovirus 71 and coxsackie B viruses.