Togaviridae

Year III
Togaviridae
• Rubivirus-rubella
• Alphavirus- Equine Encephalitis, Sindbis
• Pestivirus- animal pathogens
• bovine viral diarrhea, hog cholera

• Rubivirus
• Rubella virus is the only member of the genus Rubivirus & is the causative
agent of Rubella (German measles or 3-day measles).
• In the prevaccination era, 80% of women were already infected by
childbearing age.
Rubella virion
• The virions are pleomorphic, measuring 50-70 nm in diameter with an
icosahedral capsid.

• They possess a linear ssRNA genome (about 10kb) of positive

polarity.

• Virions acquire the envelope by budding from cell membranes into

intracytoplasmic vesicles.

• Viral replication occurs in the cytoplasm.

Postnatal Rubella-Pathogenesis
• Neonatal, childhood, and adult infections occur through the mucosa of the
upper RT by direct contact.

• Virus replication first occurs in the RT, and then in cervical lymph nodes.

• A viremia develops after 7–9 days and lasts until the appearance of Ab on
about day 13–15.

• The development of Ab coincides with the appearance of the rash,

suggesting an immunologic basis for the rash.

• In 20–50% of cases, primary infection is subclinical.

Rash of Rubella
• Maculopapular rash
• Lymphadenopathy
• Fever
• Arthropathy (up to 60% of cases)
Clinical Features

• Post-natal rubella is a mild exanthemous infection.

• The erythematous rash appear first on the face, then spread to the
trunk and limbs, and rarely lasts more than 3 days..

• In nearly half of all the infections, there is no rash at all.

• Minor pyrexia, malaise, and lymphadenopathy also occur.

Clinical Features

• Mild polyarthritis, usually involving the hands is uncommon in

children, but may occur in up to 60% of adult females.

• Encephalitis & thrombocytopenia are rare complications of rubella and

usually recovery is complete.

• Rubella appears to present little danger to the immunocompromised

patient; the clinical features are similar to those seen in
immunocompetent individuals.
Congenital rubella syndrome-Pathogenesis
• Maternal viremia associated with rubella infection during pregnancy
may result in infection of the placenta and fetus.

• Only a limited number of fetal cells become infected.

• The growth rate of infected cells is reduced, resulting in fewer

numbers of cells in affected organs at birth.

• The infection may lead to deranged and hypoplastic organ

development, resulting in structural anomalies in the newborn.
Congenital Rubella Syndrome-Pathogenesis
• Generally, the earlier in pregnancy infection occurs, the greater the damage
to the fetus.

• Infection during the first trimester of pregnancy results in abnormalities in

the infant in about 85% of cases, whereas detectable defects are found in
about 16% of infants who acquired infection during the second trimester.

• Birth defects are uncommon if maternal infection occurs after the 20th week
of gestation.
Clinical Features of Congenital Rubella

• The most frequent congenital deformities are deafness, blindness (total

or partial, especially cataracts), cardiac defects, microcephaly with
mental retardation, and spina bifida.

• In intrauterine embryo deaths due to rubella infections the immediate

cause of death is usually myocardial damage.
Control

• Attenuated live rubella virus vaccines are available (have been in use
since 1969).

• Vaccination of pregnant women is contraindicated, and pregnancy

should be avoided for the month following immunization.

• A combined measles-mumps-rubella (MMR) -1972.

Congenital Rubella Syndrome

• Classical triad consists of cataracts, heart defects, and sensorineural

deafness.

• Many other abnormalities had been described and these are divided
into transient, permanent and developmental.
• Transient: low birth weight, hepatosplenomegaly, thrombocytopenic purpura,
bone lesions, meningoencephalitis, hepatitis, haemolytic anaemia, pneumonitis,
lymphadenopathy
Congenital Rubella Syndrome

• Permanent: Sensorineural deafness, Heart Defects (peripheral pulmonary

stenosis, pulmonary valvular stenosis, patent ductus arteriosus, ventricular
septal defect) Eye Defects (retinopathy, cataract, microopthalmia,
glaucoma, severe myopia) Other Defects (microcephaly, diabetes mellitis,
thyroid disorders, dermatoglyptic abnormalities

• Developmental: Sensorineural deafness, Mental retardation, Diabetes

Mellitus, thyroid disorder
Laboratory Diagnosis
• Diagnosis of acute infection
• Rising titres of antibody (mainly IgG) - HAI, EIA

• Presence of rubella-specific IgM – EIA

• Immune Status Screen

• HAI is too insensitive for immune status screening

• SRH, EIA and latex agglutination are routinely used

• 15 IU/ml is regarded as the cut-off for immunity

Typical Serological Events Following Acute Rubella Infection

Note that in reinfection, IgM is usually absent or only present transiently at a

low level
Paramyxoviridae
• Paramyxoviruses are a family of enveloped viruses containing ssRNA
of negative polarity.

• This family includes the genera:

• Paramyxovirus with the parainfluenza viruses.
• Rubulavirus with the mumps virus.
• Morbillivirus with the measles virus.
• Pneumovirus with the respiratory syncytial virus (RSV).
• Nonclassified paramyxoviruses (Hendra, Nipah).
Parainfluenza viruses
• Clinical Features

• Parainfluenza viruses are transmitted by droplet infection.

• The parainfluenza viruses cause flulike infections, mainly in small

children, which occasionally progress to bronchitis or even
pneumonia.
Clinical Features

• Occasionally, a dangerous croup syndrome develops.

• It is due to a combination of tracheitis and laryngitis.

• The child presents with fever, a harsh brassy cough, stridor, and
respiratory distress which may occasionally progress to laryngeal
obstruction requiring intubation or tracheotomy

• There are no vaccines for the control of parainfluenza virus infections.

Mumps virus-Clinical Features

• Painful edematous enlargement of the parotid and other salivary glands

• Epididymoorchitis occurs in 25% of all mumps cases in postpubertal males

and may lead to atrophy of the affected testicle.

• Mumps meningitis is also fairly frequent.

• Complications include infection of various glandular organs (e.g. pancreas,

ovary, thyroid, and breast.

• MMR vaccine is used for the control of mumps virus infection

Measles virus-Clinical Features
• Measles is an acute febrile illness, mostly in childhood

• The onset is ‘flu-like’, with high fever, cough, and conjuctivitis.

• Koplik’s spots (red spots with a bluish white center on the buccal mucosa)
may be present at this stage.

• After 1-2 days the acute symptoms decline with the appearance of a
widespread maculopapular rash.

• Over the next 10-14 days recovery is usually complete as the rash fades
with considerable desquamation.
Measles virus-Clinical Features
• Common complications include otitis media, croup, bronchitis, &
bronchopneumonia.

• Bacterial pneumonia is the usual cause of death, particularly in

malnourished children.

• Immunologically deficient children can die from measles induced giant-cell

pneumonia or from acute progressive infectious encephalitis with no sign of
a rash.
Measles virus-Clinical Features

• Subacute sclerosing panencephalitis (SSPE) is a rare complication

(occurring in 1/300,000 cases), some years after apparent recovery
from the original infection.

• It is a progressive and inevitably fatal degenerative disease

• MMR vaccine is used for the control of measles virus infection.

Reoviridae
Introduction
• The name reovirus is derived from the abbreviation for respiratory enteric
orphan virus, recalling that no diseases were associated with the virus upon
its discovery (hence “orphan virus”).
• The family Reoviridae includes, in addition to phytopathogenic and
zoopathogenic strains, three genera in which human pathogens are
classified:
• Orthoreovirus- reovirus types 1, 2, & 3
• Coltivirus- various serogroups
• Rotavirus- classified into multiple groups (A through G), based on antigenicity and
overall genome similarity.
Enteroviruses
Year III
Introduction

• 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.
Introduction

• 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)
Background
• 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.
Background
• 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).
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)
Picornaviridae

• The important human pathogenic genera of the family Picornaviridae

are:

• Enteroviruses with the polioviruses, cocksackieviruses and

echoviruses.
• Parechoviruses types 1 and type 2.

• Hepatoviruses with the hepatitis A virus.

• Rhinoviruses, common cold viruses (rhinitis).

Poliovirus virion

• Nonenveloped icosahedral capsid, 22-30 nm in diameter.

• The genome is linear, ssRNA of positive sense.

• Virion RNA acts as mRNA and is translated into a single polypeptide,

VP0, which is cleaved proteolytically to yield nonstructural and
structural proteins.

• Viral replication occurs in the cytoplasm.

Poliovirus Features

• Polioviruses are transmitted per os and replicate at first in the lymphoid

tissue of the pharyngeal space, later mainly in the intestinal wall.

• They commonly cause asymptomatic immunizing infections which protect

against future infections with the same virus.

• They can give rise to viraemia.

• They occasionally cause infection of the CNS.

• They are commoner in children than adults.

Clinical Features of Poliovirus Infection
• Paralysis is a relatively infrequent complication of an otherwise trivial
infection.

• Poliovirus infection of the CNS may result in meningitis (from which most
patients recover completely).

• Encephalitis and/or paralytic poliomyelitis is due to virus replication in

motor neurones of the spinal cord or the brain stem, resulting in paralysis of
limbs and/or breathing muscles.

• Acquired immunity is permanent, but is monotypic

Clinical Features of Poliovirus Infection
Control
• Vaccination: 2 types of vaccines
• The dead or inactivated vaccine (IPV)
• Consists of three poliovirus types, inactivated by formalin.
• Has the advantage of a long stability period and practically foolproof
application safety.
• The disadvantages of this vaccine form are its high cost, the requirement for
three injections and weaker or at least shorter lived protection than is
provided by the attenuated form.
Control
• The advantages of the live vaccine are its oral application route, low price and
high level of efficiency.
• One disadvantage is its thermolability, resulting in reduced numbers of
seroconversions (more nonresponders) in tropical countries.
• Another difficulty is presented by the (1 in 1 * 106) cases of paralysis
(vaccination-associated paralytic poliomyelitis, VAPP) resulting from a
vaccination.
• VAPP shows a higher level of incidence than infections by the wildtype poliovirus
in industrialized countries, which has led practically all these countries to return to
using IPV.
Coxsackieviruses
• 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.
Coxsackieviruses

• 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.
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.

• Altogether, 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.
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 through Africa, Asia, India and Europe from 1969 to 1974.

• The virus is occasionally neurovirulent.

New Enteroviruses

• 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 - - + -
Disease Associations
• Paralytic Disease - most commonly associated with polioviruses but other
enteroviruses may also be responsible, notably 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.
Disease Associations

• 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 (Bornholm disease) - normally caused by group

B coxsackieviruses.
Disease Associations

• 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.
Disease Associations
• 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, notably 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
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.
Laboratory Diagnosis

• 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
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.