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 Picornaviruses
Enterovirus
Polio Diseases of the human (and other) alimentary tract
Coxsackie A and B (e.g. polio virus)
Echo
Other enteroviruses
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
Virus Serotypes Clinical Diseases

Polioviruses 3 types Asymptomatic infection, viral

meningitis, paraalytic disease,
poliomyelitis
Coxsackie A viruses 23 types ( A1-A22, Viral meningitis plus, rash,
A24) ARD, myocarditis, orchitis

Coxsackie B viruses 6 types (B1-B6) Viral meningitis, but no orchitis

Echioviruses 32 types Viral meningitis, with orchitis

Other Enteroviruses 4 types(68-71) Viral meningitis, rash,ARD

 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 enteroviruses
Property Enteroviruses
Size (nm) 22-30
Capsid
form Icosahedral
Polypeptide VP1, VP2, VP3, VP4
RNA type SS-PS
RNA molecular weight 2000,000-2600,000
Acid Stable*
Optimal temperature for growth(oC) 37
Density in caesium chloride (g/m) 1.34*
 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
Replication in
oropharynx
Rhino,echo,
coxsackie,polio Primary viremia

Target Tissue Secondary viremia

Skin Muscle Brain Meninges Liver

Echo Echo Polio Echo Echo

Coxsackie Coxsackie Coxsackie Polio Coxsackie
A A, B 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

+ Paralysis
Coxsackie 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 Enteroviruses
Syndrome 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.