Medical biology, microbiology,
virology, immunology department
By as. E.V. Pokryshko
Genera of Picornaviruses
Enterovirus
Polio, types 1-3
Coxsackie A ,
1-24
types
Diseases of the human (and other) alimentary
tract (e.g. polio virus)
Coxsackie B, types 1-6
Echo, types 1-34
Other enteroviruses,
types 68-71
Rhinovirus,
types 1-115
Cardiovirus
Aphthovirus
Hepatovirus
Others
Disease of the nasopharyngeal region (e.g.
common cold virus)
Murine encephalomyocarditis, Theiler's murine
encephalomyelitis virus
Foot and mouth disease in cloven footed
animals
Human hepatitis virus A
Drosophila C virus, equine rhinoviruses, cricket
paralysis virus
Pathogenesis of enterovirus infection
Replication in
oropharynx
Rhino,echo,
coxsackie,polio
Primary viremia
Secondary viremia
Target Tissue
Skin
Muscle
Brain
Meninges
Liver
Echo
Echo
Polio
Echo
Echo
Coxsackie
Coxsackie
Coxsackie
Polio
Coxsackie
A
A, B
Coxsackie
Clinical Picornavirus Syndromes
Virus
Polioviruses
(types 1-3)
Diseases (Virus Type)
Undifferentiated febrile illnesses
(types 1-
3)
Aseptic memingitis (types 1-3)
Paralisis and encephalitic
diseases
(types 1-3)
Coxsackievirus
group A
(A1-A, A-24)*
Acute hemorrhagic conjunctivitis (type 24)
Herpangina (types 2-6, 8, 10, 22)
Exanthem (types 4, 5, 6, 9, 16)
Hand-foot-mouth disease (types 5, 10, 16)
Aseptic memingitis (types 1, 2, 4-7, 9, 10, 14,
16, 22)
Paralysis and encephalitic diseases
(occasional types 4, 7, 9, 10)
Hepatitis (types 4, 9)
Virus
Diseases (Virus Type)
Upper and lower respiratory illnesses
Coxsackievirus
9, 10, 16, 21, 24)
group A (A1-A, A- (types
Lymphonodular pharyngitis (10)
24)*
Infantile diarrhea (types 18, 20, 21, 22, 24
variant)
Undifferentiated febrile illnesses
(types 1-
6)
Pleurodinia (types 1-5)
Pericarditis, myocarditis (types 1-5)
Aseptic meningitis types (1-6)
Paralysis and encephalitic diseases
(occasional types 1-5)
Severe systemic infection in infants,
meningoencephalitis and myocarditis
(types 1-5)
Upper and lower respiratory
illnesses
(types 4, 5)
Exanthem, hepatitis, diarrhea (types 5)
Virus
Echoviruses
(1-7, 9, 11,
29-33)*
Diseases (Virus Type)
Aseptic meningitis (many seroypes )
Paralysis and encephalitic diseases
(occasional types 1, 2, 4, 6, 7, 9, 11, 14-16, 18, 22,
30)
Exanthem
(types 1-9, 11, 14, 16, 18, 19, 25, 30,
32)
Hand-foot-mouth disease (19)
Pericarditis, myocarditis (types 1, 6, 9,
19,
22)
Upper and lower respiratory illnesses
(types 4, 9, 11, 20, 22, 25)
Neanatal diarrhea (types 11, 14, 18, 20, 32)
Epidemic mialgia (types 1, 6, 9)
Hepatitis (types 4, 9)
Virus
New
enteroviruses
Diseases (Virus Type)
Pneumonia and bronchiolitis
(types
68, 69)
Acute
hemorrhagic
conjunctivitis
(type 70)
Rhinoviruses
(1-115)
Hepatovirus
(Hepatitis A)
Aseptic meningitis,
meningoencephalitis
Hand-foot-mouth disease (71)
Hepatitis (type 72)
Upper and lower respiratory
illnesses (types 1-115)
Gastroenteritis and hepatitis A
* Reclassification of coxsackievirus A23 as echovirus 9, echovirus 8 as 1, echovirus 10 as
reovirus, echovirus 28 as rhinovirus type 1A, and echovirus 34 as coxsackievirus A24.
RNA
Properties
of enteroviruses
Property
Enteroviruses
Size (nm)
Capsid form
Polypeptide
RNA type
Acid
22-30
Icosahedral
VP1, VP2, VP3, VP4
‘+’, single stain
Stable
Optimal temperature for
growth(oC)
37
POLIOMYELITIS




“Picornavirus”
3 types: Poliovirus
1,2,3
Ingested, spread by
alimentary route:
Commoner in areas of
poor sanitation
Infants protected by
maternal antibodies
Poliomyelitis is an acute infectious
disease that in its serious form affects
the central nervous system. The
destruction of motor neurons in the
spinal cord results in flaccid paralysis
(less than 0.1%). However, most
poliovirus infections are subclinical.
During epidemic outbreaks, type I is
most frequently isolated (in 65-95 per
cent of cases) while types II and III
account for the remaining 5-35 per cent
of cases.
Morphology.
The virus is 30 nm in size and forms
intranuclear
inclusions.
The
virion
is
icosahedral and consists of a single sensestrand RNA and a protein capsid containing
32 spherical subunits (capsomeres).
This genome RNA serves as an mRNA and
initiates
the
synthesis
of
virus
macromolecules.
The poliomyelitis virus has neither an outer
membrane nor lipids and is therefore not
sensitive to the effect of ether and sodium
desoxycholate.
Morphology.
Poliomielitis virus
Cultivation. SPE.
The poliomyelitis virus is
cultivated on kidney cells of
green African monkeys and on
diploid human cells devoid of
latent SV40 viruses.
The cytopathic effect is
attended by destruction and the
formation of granules in the
infected cells.
Resistance.
The
virus
is
extremely
resistant
to
photodynamic inactivation. It survives in sterile
water at room temperature for a period of more
than 100 days, in milk for 90 days, in faeces in the
cold for more than 6 months, and in sewage for
several months. It withstands exposure to 0.5-1
per cent phenol solutions and remains viable for
several weeks at pH 3.8-8.5.
The poliomyelitis virus is sensitive to calcium
chlorate lime, chloramine, formalin, potassium
permanganate, and hydrogen peroxide solutions.
It is rapidly killed on boiling.
Pathogenesis
Source
of infection: Apparent and
subclinical patients
Incubation: is usually 7-14 days, but it may
range from 3 to 35 days.
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
1. The mouth is the portal of entry of the virus.
2. The virus first multiplies in the tonsils, the lymph nodes of
the neck, Peyer's patches, and the small intestine.
The virus is regularly present in the throat and in the stools
before the onset of illness. One week after onset there is little
virus in the throat, but virus continues to be excreted in the stools
for several weeks, even though high antibody levels are present in
the blood.
3. Viremia
The virus may be found in the blood of patients with abortive
and nonparalytic poliomyelitis.
4. The central nervous system may then be invaded by way of
the circulating blood.
Pathogenesis
Poliovirus can spread along axons of peripheral nerves to the
central nervous system, and there it continues to progress along
the fibers of the lower motor neurons to increasingly involve the
spinal cord or the brain. Poliovirus invades certain types of nerve
cells, and in the process of its intracellular multiplication it may
damage or completely destroy these cells. The anterior horn cells of
the spinal cord are most prominently involved, but in severe cases
the intermediate gray ganglia and even the posterior horn and dorsal
root ganglia are often involved. In the brain, the reticular formation,
vestibular nuclei, and deep cerebellar nuclei are most often affected.
The cortex is virtually spared, with the exception of the motor cortex
along the precentral gyms.
Clinical Findings. When an individual
susceptible to infection is exposed to the
virus, one of the following responses may
occur:
 inapparent infection without symptoms
(asymptomatic illness), the minor illness –
90% infected people
 aseptic meningitis – 1%-2% of patients
with poliovirus infections,
 paralytic poliomyelitis, the major illness
0.1% to 2% of persons with poliovirus
Only about 1%
recognized clinically.
of
infections
are
Abortive Poliomyelitis. This is the
commonest form of the disease. The
patient has only the minor illness,
characterized by fever, malaise,
drowsiness, headache, nausea, vomiting,
constipation, and sore throat in various
combinations. The patient recovers in a
few days. The diagnosis of abortive
poliomyelitis can be made only when the
virus
is
isolated
or
antibody
development is measured.
Nonparalytic Poliomyelitis (Aseptic
Meningitis). In addition to the above
symptoms and signs, the patient with
the
nonparalytic
form
presents
stiffness and pain in the back and neck.
The disease lasts 2-10 days, and
recovery is rapid and complete. In a
small percentage of cases, the disease
advances to paralysis.
Paralytic Poliomyelitis. The major
illness usually follows the minor illness
described above, but it may occur
without the antecedent first phase.
The predominating complaint is flaccid
paralysis resulting from lower motor
neuron damage. The maximal recovery
usually occurs within 6 months, with
residual paralysis lasting much longer.
Child with polio sequelae
Immunity
sIgA and neutralizing antibody (IgG, IgA,
IgM) persist for life span
Immunity is permanent to the type
causing the infection. There may be a low
degree of heterotypic resistance induced
by infection, especially between type 1
and type 2 polioviruses.
Passive immunity is transferred from
mother to offspring. The maternal
antibodies gradually disappear during the
first 6 months of life. Passively
administered antibody lasts only 3-5
weeks.
Lab Diagnosis
Definitive diagnosis is made by osolation of
the virus from stool, CFS, oropharyngeal
secretions
 Cell culture involves fibroblastic MRC-5 cells
CPE is usually evident within 36 hours
 Serotyping is based on neutralization of CPE
by standardized antisera using intersecting
pool followed by specific sera.
 ELISA
 IFA
 neutralizing Test
 CFT

Treatment
There is no specific treatment. Treatment involves
reduction of pain and muscle spasm and maintenance of
respiration and hydration. When the fever subsides,
early mobilization and active exercise are begun. There
is no role for antiserum. Early injections of gammaglobulin, blood transfusion, wide use of vitamins C and
B,-, amino acids (leucine, glutamic acid), analgesics
(analgine, amidopyrine, pantopon, etc.), mediators, and
stimulants (proserine, galanthamine, dibazol, etc.) are
recommended. An orthopaedic regimen is set up from
the first day that paralysis develops to prevent
contractures and deformations, and exercise therapy is
carried out during the rehabilitation period. An
apparatus for artificial respiration is employed when
there are respiration disturbances.
Prevention
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
Both killed and live virus vaccines induce
antibodies and protect the central
nervous system from subsequent
invasion by wild virus. Low levels of
antibody resulting from killed vaccine
have little effect on intestinal carriage
of virus. The gut develops a far greater
degree of resistance after live virus
vaccine, which seems to be dependent
on the extent of initial vaccine virus
multiplication in the alimentary tract
rather than on serum antibody level.
Advantages and disadvantages of OPV
Advantages
 Effectiveness
 Lifelong
immunity
 Induction of secretory antibody
response similar to that of natural
infection
 Possibility of attenuated virus
circulating in community by spread to
contacts (indirect immunization)(herd
immunity)
 Ease of administration
 Lack of need for repeated boosters
Advantages and disadvantages of OPV
 Risk
Disadvantages
of vaccine-associated
poliomyelites in vaccine recipients or
contacts
 Spread of vaccine to contacts without
their consent
 Unsafe administration for
immunodeficient patients
Advantages and disadvantages of IPV
Advantages
 Effectiveness
 Good
stability during transport and in
storage
 Safe administration in
immunodeficient patients
 No risk of vaccine-related disease
Advantages and disadvantages of IPV
 Lack
Disadvantages
of induction of local (gut)
immunity
 Need for booster vaccine for lifelong
immunity
 Fact that injection is more painful
than oral administration
 Fact that higher community
immunization levels are needed than
with live vaccine
COXSACKIEVIRUSES
The coxsackieviruses comprise a large
subgroup of the enteroviruses. They
produce a variety of illnesses in human
beings, including aseptic meningitis,
herpangina, pleurodynia, hand, foot, and
mouth disease, myo- and pericarditis,
common colds, and possibly diabetes.
Coxsackieviruses have been divided
into 2 groups, A and B, having different
pathogenic potentials for mice.
Group A viruses produce widespread myositis
in the skeletal muscles of newborn mice,
resulting in flaccid paralysis without other
observable lesions.
Group B viruses may produce spasticity effect
in sucking mice, focal myositis, encephalitis,
and, most typically, necrotizing steatitis
involving mainly fetal fat lobules. Some B
strains also produce pancreatitis, myocarditis,
endocarditis, and hepatitis in both suckling and
adult mice.
Normal adult mice tolerate infections with
group B coxsackieviruses.
Herpangina: There is an abrupt onset of fever, sore
throat, anorexia, dysphagia, vomiting, or abdominal pain. The
pharynx is usually hyperaemic, and characteristic discrete
vesicles occur on the anterior pillars of the fauces, the
palate, uvula, tonsils, or tongue. The illness is self-limited
and most frequent in small children.
Exanthems – Rubelliform rashes
Hand, Foot, and Mouth Disease: The syndrome is
characterized by oral and pharyngeal ulcerations and a
vesicular rash of the palms and soles that may spread to the
arms and legs. Vesicles heal without crusting, which clinically
differentiates them from the vesicles of herpes- and poxviruses. The rare deaths are caused by pneumonia.
Hand-foot-and-mouth disease

Hand-foot-and-mouth
disease: mostly coxackie A

fever, malaise, sore
throat, vesicles on bucсal
mucosa, tongue, hands,
feet, buttocks

highly infectious

resolution – 1w
ECHOVIRUSES
The echoviruses (enteric cytopathogenic human orphan
viruses) are grouped together because they infect the
human enteric tract and because they can be recovered
from humans only by inoculation of certain tissue cultures.
Over 30 serotypes are known, but not all cause human
illness. Aseptic meningitis, febrile illnesses with or without
rash, common colds, and acute hemorrhagic conjunctivitis
are among the diseases caused by echoviruses.
Properties of the Viruses
General
Properties.
Echoviruses
enteroviruses measuring 24-30 nm.
are
typical
Important Characteristics
Not produce diseases in sucking
mice, rabbits, or monkeys;
 Cause aseptic meningitis, infantile
diarrhea,
 Monkey kidney and human
embryonated kidney cell culture

Growth of Virus. Monkey kidney cell culture is the method of
choice for the isolation of these agents. Some also multiply in
human amnion cells and cell lines such as HeLa.
Certain echoviruses agglutinate human group 0 erythrocytes.
The hemagglutinins are associated with the infectious virus
particle but are not affected by neuraminidase.
Initially, echoviruses were distinguished from coxsackieviruses
by their failure to produce pathologic changes in new-born
mice, but echovirus-9 can produce paralysis in new-born
mice. Conversely, strains of some coxsackievirus types
(especially A9) lack mouse pathogenicity and thus resemble
echoviruses. This variability in biologic properties is the chief
reason why new enteroviruses are no longer being
subclassified as echo- or coxsackieviruses,
Antigenic Properties. Over 30 different antigenic types
have been identified. The different types may be separated
on the basis of cross-Nt or cross-CF tests. Variants exist
that do not behave exactly like the prototypes. After human
infections, Nt antibodies persist longer than CF antibodies.
Animal Susceptibility. To be included in the echo group,
prototype strains must not produce disease in suckling
mice, rabbits, or monkeys. In the chimpanzee, no apparent
illness is produced, but infection can be demonstrated by
the presence and persistence of virus in the throat and in
the feces and by the type-specific antibody responses.
Epidemiology. The epidemiology of echoviruses is similar to
that of other enteroviruses. They occur in all parts of the
globe. Unlike the enterobacteria, which are constantly present
in the intestinal tract, the enteroviruses produce only transitory
infections. They are more apt to be found in the young than in
the old. In the temperate zone, infections occur chiefly in
summer and autumn and are about 5 times more prevalent in
children of lower income families than in those living in more
favourable circumstances.
Studies of families into which enteroviruses were introduced
demonstrate the ease with which these agents spread and the
high frequency, of infection in persons who had formed no
antibodies from earlier exposures. This is true for all
enteroviruses.
Wide dissemination is the rule. In a period when 149
inhabitants of a city of 740,000 were hospitalized with echo-9
disease, approximately 6% of the population, or 45,000
persons, had a compatible illness.
Pathogenesis & Pathology. The pathogenesis of the
alimentary infection is similar to that of the other
enteroviruses. Virus may be recovered from the throat
and stools: in certain types (4, 5. 6, 9, 14. and IS)
associated with aseptic meningitis, the virus has been
recovered from the cerebrospinal fluid.
Clinical Findings. To establish etiologic association of
echovirus with disease, the following criteria are used; (1)
There is a much higher rate of recovery of virus from
patients with the disease than from healthy individuals of
the same age and socioeconomic level living in the same
area at the same time. (2) Antibodies against the virus
develop during the course of the disease. If the clinical
syndrome can be caused by other known agents, then
virologic or serologic evidence must be negative for
concurrent infection with such agents. (3) The virus is
isolated from body fluids or tissues manifesting lesions,
e.g., from the cerebrospinal fluid in cases of aseptic
meningitis.
Echoviruses 4, 6, 9, 11, 14, 16, 18, and others have been
associated with aseptic meningitis. Rashes are common in
types 9, 16 ("Boston exanthem disease"), 18, and 4.
Rashes are commonest in young children. Occasionally,
there is conjunctivitis, muscle weakness, and spasm (types
6,9, and others). Infantile diarrhea may be associated with
some types (e.g., 18, 20). Echovirus type 28 isolated from
upper respiratory illness causes "colds" in volunteers and
has been reclassified as rhinovirus type 1. For many
echoviruses (and some coxsackieviruses), no disease
entities have been defined.
With the virtual elimination of polio in developed countries,
the central nervous system syndromes associated with
echo- and coxsackieviruses have assumed greater
prominence. The latter in children under age 1 may lead to
neurologic sequelae and mental impairment. This does not
appear to happen in older children.
Laboratory Diagnosis
It is impossible in an individual case to diagnose an echovirus
infection on clinical grounds. However, in the following epidemic
situations, echoviruses must be considered: (1) summer outbreaks of
aseptic meningitis; (2) summer epidemics, especially in young
children, of a febrile illness with rash; and (3) outbreaks of diarrheal
disease in young infants from whom no pathogenic enterobacteria can
be recovered.
The diagnosis is dependent upon laboratory tests. The procedure of
choice is isolation of virus from throat swabs, stools, rectal swabs,
and, in aseptic meningitis, cerebrospinal fluid. Serologic tests are
impractical — because of the many different virus types — unless a
virus has been isolated from a patient or during an outbreak, of typical
clinical illness. Nt and HI antibodies are type-specific and may persist
for years. CF antibodies give many heterotypic responses.
If an agent is isolated in tissue culture, it is tested against different
pools of antisera against enteroviruses. Determination of the type of
virus present depends upon neutralization by a single serum. Infection
with 2 or more enteroviruses may occur simultaneously.
Control. Avoidance of contact with patients exhibiting
acute febrile illness, especially those with a rash, is
advisable for very young children. Members of
institutional staffs responsible for caring for infants should
be tested to determine whether they are carriers of
enteroviruses. This is particularly important during outbreaks of diarrheal disease among infants.
OTHER ENTEROVIRUS TYPES
Four enteroviruses (types 68-71) grow in monkey kidney
cultures, and 3 of them cause human disease.
Enterovirus 68 was isolated from the respiratory tracts of children
with bronchiolitis or pneumonia.
Enterovirus 70 is the chief cause of acute hemorrhagic
conjunctivitis. It was isolated from the conjunctiva of patients with
this striking eye disease, which occurred in pandemic form in
1969-1971 in Africa and Southeast Asia. It was not diagnosed in
the USA until its importation into Florida in 1981. Acute
hemorrhagic conjunctivitis has a sudden onset of subconjunctival
hemorrhage ranging from small petechiae to large blotches
covering the bulbar conjunctiva. There may also be epithelial
keratitis and occasionally lumbar radiculomyelopathy. The
disease is commonest in adults, with an incubation period of 1
day and a duration of 8-10 days. Complete recovery is the rule.
The virus is highly communicable and spreads rapidly under
crowded or unhygienic conditions. There is no effective
treatment.
Enterovirus 71 was isolated from patients with meningitis,
encephalitis, and paralysis resembling poliomyelitis. It
continues to be one of the main causes of central nervous
system disease, sometimes fatal, around the world. In
some areas, particularly in Japan and Sweden, the virus
has caused outbreaks of hand, foot, and mouth disease.
RHINOVIRUS GROUP
Rhinoviruses are isolated commonly from the nose and
throat but very rarely from feces. These viruses, as well as
coronaviruses and some reo-,
adeno-, entero-,
parainfluenza, and influenza viruses, cause upper
respiratory tract infections, including the "common cold."
General Properties: Rhinoviruses are picornaviruses
similar to enteroviruses but differing from them in having a
CsCI buoyant density of 1.40 g/mL and in being acid-labile.
Animal Susceptibility and Growth of Virus. These viruses
are infectious only for humans and chimpanzees. They have
been grown in cultures of human embryonic lung fibroblasts
(WI-38) and in organ cultures of ferret and human trachea!
epithelium. They are grown best at 33 °C in rolled cultures.
Antigenic Properties: Over 100 serotypes are known. Some
cross-react (e.g., types 9 and 32).
Pathogenesis & Pathology. The virus enters via the upper
respiratory tract. High titers of virus in nasal secretions —
which can be found as early as 2-4 days after exposure – are
associated with maximal illness. Thereafter, viral titers fall,
although illness persists.
Histopathologic changes are limited to the submucosa and
surface epithelium. These include engorgement of blood
vessels, oedema, mild cellular infiltration, and desquamation
of surface epithelium, which is complete by the third day.
Nasal secretion increases in quantity and in protein
concentration.
Experiments under controlled conditions have shown that
chilling, including the wearing of wet clothes, does not
produce a cold or increase susceptibility to the virus.
Chilliness is an early symptom of the common cold.
Epidemiology. The disease occurs throughout the world. In
the temperate zones, the attack rates are highest in early fall
and winter, declining in the late spring. Members of isolated
communities form highly susceptible groups.
The virus is believed to be transmitted through close contact,
by large droplets. Under some circumstances, transmission of
the virus by self-inoculation through hand contamination may
be a more important mode of spread than that by airborne
particles.
Colds in children spread more easily to others than do colds in
adults. Adults in households with a child in school have twice
as many colds as adults in households without school
children.
In a single community, many rhinovirus serotypes cause
outbreaks of disease in a single season, and different
serotypes predominate during different respiratory disease
seasons.
Clinical Findings. The incubation period is brief, from 2 to
4 days, and the acute illness usually lasts for 7 days
although a non-productive cough may persist for 2-3
weeks. The average adult has 1-2 attacks each year.
Usual symptoms in adults include irritation in the upper
respiratory tract, nasal discharge, headache, mild cough,
malaise, and a chilly sensation. There is little or no fever.
The nasal and nasopharyngeal mucosa become red and
swollen, and the sense of smell becomes less keen. Mild
hoarseness may be present. Prominent cervical
adenopathy does not occur. Secondary bacterial infection
may produce acute otitis media, sinusitis, bronchitis, or
pneumonitis, especially in children. Type-specific
antibodies appear or rise with each infection.