Transcript Gastrointestinal Viruses

21 Enterovirus
Structure and composition
The virion of enterovirus consists of
a capsid shell of 60 subunites ,each
of four proteins(vp1-vp4)arranged
with icosahedral symmetry around a
genome made up of a single strand
of positive –sense RNA.
Morphology
27nm, icosahedral symmetry, no
envelope
The molecular structure :
The three largest viral proteins,vp1-vp3,have
a very similar core structure, in which the
peptide backbone of the protein loops back on
itself to form a barrel of eight strands held
together by hydrogen bonds(the beta barrel).
The amino acid chain between the beta
barrel and the N and C terminal proteins of the
protein contains a series of loops. These loops
include the main antigenic sites that are found
on the surface of the viron and involved in the
neutralization of viral infection.
The genome RNA is in size about 7.4kb .The
genome is polyadenylated at the 3` end and has
a small viral coded protein(VPg) covalently
bound to the 5`end. The positive-sense genomic
RNA is infectious.
Enterovirus structure
Surface cleft – attachment to cellular receptors:
Immunoglobulin superfamily, integrins, ICAM-1
Classification
Enteroviruses include the following :
(1)polioviruses,type 1-3;
(2) coxsakieviruses of group A, types 1-24 (there
is no type 23);
(3) coxsakieviruses of group B, types 1-6;
(4) echoviruses, types 1-33 (no types 10,22,23,or
28);
(5) enteroviruses, types 68-71.
Enteroviruses Serotypes
肠道病毒的特点
 小球形病毒（~ 30 nm），无包膜
 核酸为+ssRNA，有感染性
 衣壳有VP1—VP4四种蛋白，VP1—VP3分布在
表面，VP4与内部RNA结合
 耐酸耐乙醚，但鼻病毒除外
 在胞浆增殖，有明显CPE，破胞释放
 引起多种疾病：麻痹性疾病、无菌性脑膜炎、
心肌损伤、腹泻、皮疹等
Poliovirus
Poliovirus was 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
Poliovirus may cause poliomyelitis ,
which is an infectious disease that in its
serious form affects the central nervous
system. However, most poliovirus infections are subclinical.
General properties:
Poliovirus particle are typical enterovirus.
They are inactivated when heated at 550c for
30min,by a chlorine concentration of 0.1ppm
Poliovirus are not affected ether or sodium
deoxycholate
Animal susceptibility and
growth of virus:
Polioviruses have a very restricted host
range .Most strains will infect monkeys
when inoculated directly into the brain
or spinal cord.
Most strains can be grown in primary or
continuous cell line cultures derived from
a variety of human tissues or from monkey kidney, testis, or muscle ,but not from
tissues of lower animals.
Antigenic propertis:
There are three antigenic types
Two type-specific Ag (D and C)are
contained in poliovirus preparation
and can be detected by ELISA.
The D form can be converted to the C
form by heating . The D form represents full particles containing RNA; the
C form ,empty particles.
Pathogenesis ﹠ Pathology:
The mouth is the portal of entry of the virus
and primary multiplication takes place in
the oropharynx or intestine.
The virus is regularly present in the throat
and in the stools before the onset of illness.
The virus may be found in the blood of
patients with nonparalytic poliomyelitis. Ab
to the virus appear early in the disease,
usually before paralysis occurs
The virus first multiplies in tonsil, the lymph nodes of
the neck, Peyer’ s paches, and the small intestine.
The central nervous system may be invaded by way of
the circulating blood. Large amounts of anti-body are
necessary to prevent passage of the virus along nerve
fiber.
Poliovirus can spread along axons of peripheral nerves to the central nervous system, along the fibers of
the lower motor neurons to the spinal cord or the brain.
Virus invades certain types of nerve cell, and may damage or completely destroy these cells for its intracellular multiplication.
Transmission
 Fecal – oral route
via hands and objects
via food and water
Clinical findings:
Abortive poliomyelitis
Nonparalytic poliomyelitis
Paralytix poliomyelitis
Progressive postpoliomylitis muscle atrophy
Clinical Manifestations
 Most infections asymptomatic, 95%
 Abortive polio (minor illness), 5%: fever, malaise, sore throat,
myalgia, headache)
 Aseptic meningitis (non paralytic polio), 1%
 Paralytic polio (major illness), 0.1%: asymetric flaccid paralysis /
paresis. Lower, or upper extremities, thoracic, abdominal, bulbar.
Involvement : spinal cord anterior horn cells, motor cortex, dorsal
root ganglia
neurologic sequela (2/3)
 Post-polio syndrome: progressive atrophy years later
 Perhaps the first written
record of a virus
infection consists of a
heiroglyph from
Memphis, drawn in
approximately 1400BC,
which depicts a temple
priest called Siptah
showing typical clinical
signs of paralytic
poliomyelitis
Victims of paralytic polio
Child with polio sequelae
Franklin D. Roosevelt
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Born in 1882 at Hyde Park, New York--now a
national historic site--he attended Harvard
University and Columbia Law School. On St.
Patrick's Day, 1905, he married Eleanor
Roosevelt.
Following the example of his fifth cousin,
President Theodore Roosevelt, whom he
greatly admired, Franklin D. Roosevelt
entered public service through politics, but
as a Democrat. He won election to the New
York Senate in 1910. President Wilson
appointed him Assistant Secretary of the
Navy, and he was the Democratic nominee
for Vice President in 1920.
In the summer of 1921, when he was 39,
disaster hit-he was stricken with
poliomyelitis. Demonstrating indomitable
courage, he fought to regain the use of his
legs, particularly through swimming. At the
1924 Democratic Convention he dramatically
appeared on crutches to nominate Alfred E.
Smith as "the Happy Warrior." In 1928
Roosevelt became Governor of New York.
He was elected President in November 1932,
to the first of four terms.
Laboratory diagnosis:
The virus may be recovered from throat swabs,
rectal swabs, or stool samples.
Specimens should be kept frozen during transit
to the laboratory
Cultures of human or monkey cells
Paired serum specimens are required to show
rise in antibody titer during the course of
disease.
Laboratory Diagnosis
 Virus Isolation
 Mainstay of diagnosis of poliovirus infection
 poliovirus can be readily isolated from throat swabs,
faeces, and rectal swabs, but rarely 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
Immunity:
Immunity is permanent to the type causing the infection.
Passive immunity is transferred from
mother to offspring, which gradually
disappear during the first 6 months of
life.
Virus-neutralizing antibody forms soon
after exposure to the virus, often before
the onset of illness.
Epidemiology:
Poliomyelitis occurs worldwide – year-round
in tropics and during summer and fall in temperate zone. Winter outbreaks are rare.
The disease occurs in all age groups ,but children are more susceptible than adult because
of the acquired immunity of the adult population.
Human are the only known reservoir of infection.
Prevention ﹠ control:
Both live-virus and killed-virus vaccines are available . They induce antibody and protect the central
nervous system from subsequent invasion by wild
virus.
A potential limiting factor for oral vaccine is interference, and for vaccine-associated disease, a switch to
the use of only inactivated poliovaccine (four doses)
for children
Immune globulin can provide protection for a few
weeks against the paralytic disease but does not
prevent subclinical infection.
The application of recombinant DNA
Vaccines Available
 Intramuscular Poliovirus Vaccine (IPV)
 consists of formalin inactivated virus of all 3 poliovirus
serotypes (Salk)
 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 (Sabin).
 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%.
 OPV is used for the WHO poliovirus eradication
campaign
 Because of the slight risk of paralytic poliomyelitis,
some Scandinavian countries have reverted to using
IPV. Because of the lack of local immunity, small
community outbreaks of poliovirus infections have
been reported
Current Status of Wild Poliovirus Transmission
 我国政府规定每年12月5日和1月5日为脊灰
疫苗日。
柯萨奇病毒（Coxsackievirus）
 从1948年美国纽约州Coxsackie镇一名疑似脊髓灰质炎
的患儿粪便中用乳鼠接种的方法分离发现
 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
 Coxsackieviruses are distinguished from other
enteroviruses by their pathogenicity for suckling rather
than adult mice. They are divided into 2 groups on the
basis of the lesions observed in suckling mice.
 Group A viruses (23 types) produce a diffuse myositis
with acute inflammation and necrosis of fibers of
voluntary muscles.
 Group B viruses (6 types) 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.
 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.
Pathogenesis
 Fecal-Oral route trasmission
 Spread in the body like polioviruses
Disease Associations
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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.
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.
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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,
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.
Exanthems - Rubelliform rashes
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- EV leading cause in summer & fall. All types of rash
Hand-foot-and-mouth disease
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Hand-foot-and-mouth
disease: mostly coxackie A
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fever, malaise, sore throat,
vesicles on bucal mucosa,
tongue, hands, feet, buttocks
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highly infectious
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resolution – 1w
Herpangina
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Herpangina – usually coxackie A
 acute onset, fever, sore throat,
dysphagia
 lesions – posterior pharynx
 can persist w’s
 no gingivitis
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
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.
Echoviruses
 The first echoviruses were accidentally
discovered in 1951 from 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.
Types
 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.
Pathogenesis
 致病性与柯萨奇病毒类似，呈多样性。主要
是无菌性脑炎、类脊髓灰质炎等
 感染后对同型病毒可产生持久免疫
 诊断困难，对可疑患者可采粪便、CSF等标
本做病毒分离和中和试验
 尚无疫苗。预防以隔离为主
New Enteroviruses
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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.
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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.
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Enterovirus 71 appears to be highly pathogenic and has been
associated with epidemics of a variety of acute diseases,
including aseptic meningitis, encephalitis, paralytic poliomyelitislike disease and hand-foot-mouth disease.
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Enterovirus 72 was originally assigned to hepatitis A virus, but it
had now been assigned to a new family called heptoviruses.
Gastrointestinal Viruses
Viral Gastroenteritis
 It is thought that viruses are responsible for up to
3/4 of all infective diarrhoeas.
 Viral gastroenteritis is the second most common
viral illness after upper respiratory
infection.
tract
 In developing countries, viral gastroenteritis is a
major killer of infants who are undernourished.
Rotaviruses are responsible for half a million
deaths a year.
 Many different types of viruses are found in the
gut but only
gastroenteritis.
some
are
associated
with
Associated with gastroenteritis
 Rotaviruses
 Adenoviruses 40 41
 Caliciviruses
 Norwalk like viruses or SRSV (Small Round
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Structured Viruses)
Astroviruses
SRV (Small Round Viruses)
Coronaviruses
Toroviruses
Found in the gut, not normally
associated with gastroenteritis
 Polio
 Coxsackie A
 Coxsackie B
 Echo
 Enteroviruses 68-71
 Hepatitis A
 Hepatitis E
 Adenoviruses 1-39
 Reoviruses
Found in the gut as opportunistic
infection
 CMV
 HSV
 VZV
 HIV
Gastrointestinal Viruses
Virus
Genome
Rotaviruses:
Group A, B,
C
Typical disease
incubation
Duration
ds-segmented Major cause of
RNA
diarrhea in children
1-3 days
24-56 h
5-8 days
3-7 days
Caliciviruses
Norwalk
agents
ssRNA
Infects adults and
children
Epidemic viral
gastroenteritis
1-3 days
18-24 h
1-3 days
12-48 h
EAd 40,41
Linear
dsRNA
diarrhea in
children
7-8 days
8-12 d
Astrovirus
+ssRNA
Infects mainly
children and elderly
1-4 days
1-4 d
Gastrointestinal Viruses
 Infants:
Rotavirus A; Adenovirus 40,41;
Coxsackie A24 virus
 Infants, children, and adults
Norwalk virus; Calicivirus嵌杯样病毒属;
astrovirus; Rotavirus B; Reovirus.
Human Rotavirus
Important Characteristics
 70 nm round,
double
shelled,
enclosing a
genome of 11
segments of
double
stranded RNA.
Groups of Rotaviruses
 Group A subtypes 1, 2, 3, 4 (main
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human pathogens)
(Further 7 subtypes) also infect animals
(monkey, calf, mouse)
Group B Infects pigs and rats
Found to cause extensive outbreaks in
China in past decade
Group C Infects Pigs (Occasionally Man)
Group D Infects birds
Group E Infects pigs
Pathogenesis
 Essentially an ingestion disease (faecal-oral
route)
Incubation is short : 1 to 3 days
 Illness: Sudden onset watery diarrhoea, with or
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without vomiting. May last up to 6 days (or
longer if immunocompromised). The disease is
self limiting.
 Complications: Dehydration may result, this
can be severe and life threatening in young
children.
Pathogenesis
 Group A: Main pathogen of
infantile diarrhea
 Group B : Cause epidemic
adult diarrhea
 Group C: Cause human or
animal sporadic diarrhea
Immunity: sIgA
Lab. Diagnosis
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IEM,
Cell culture,
PAGE of RNA segments,
PCR
Latex agglutination
Elisa
Treatment
 Treatment is aimed at prevention and/or
treatment of dehydration by oral and/or
intravenous fluids and electrolytes
Prevention
 Non specific factors: improved hygiene,
education, clean water
Specific - Breast feeding helps to provide
passive immunity in the newborn (from
maternal antibodies),
Vaccination is still experimental.
Enteric Adenoviruses
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Naked DNA viruses, 75 nm in diameter.
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Fastidious enteric adenovirus types 40 and 41 are associated
with gastroenteritis.
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Associated with cases of endemic gastroenteritis, usually in
young children and neonates. Can cause occasional outbreaks.
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Possibly the second most common viral cause of gastroenteritis
(7-15% of all endemic cases).
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Similar disease to rotaviruses
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Most people have antibodies against enteric adenoviruses by
the age of three.
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Diagnosed by electron microscopy or by the detection of
adenovirus antigens in faeces by ELISA or other assays.
Astroviruses
 Small RNA viruses, named because of star-shaped surface
morphology, 28 nm in diameter.
 Associated with cases of endemic gastroenteritis, usually in
young children and neonates. Can cause occasional
outbreaks.
 Responsible for up to 10% of cases of gastroenteritis.
 Similar disease to rota and adenoviruses.
 Most people have antibodies by the age of three.
 Diagnosed by electron microscopy only, often very difficult
because of small size.
Caliciviruses
 Small RNA viruses, characteristic surface morphology
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consisting of hollows. particles 35 nm in diameter.
Associated
mainly
with
epidemic
outbreaks
of
gastroenteritis, although occasionally responsible for
endemic cases.
Like Norwalk type viruses, vomiting is the prominent
feature of disease.
Majority of children have antibodies against caliciviruses by
the age of three.
Diagnosed by electron microscopy only, often difficult to
diagnose because of small size.
Norwalk-like
Viruses
 Small RNA viruses, with ragged surface, 35 nm in diameter,
now classified as caliciviruses.
 Always
associated
with
epidemic
outbreaks
of
gastroenteritis, adults more commonly affected than children.
 Associated with consumption of shellfish and other
contaminated foods. Aerosol spread possible as well as
faecal-oral spread.
 Also named "winter vomiting disease", with vomiting being
the prominent symptom, diarrhoea usually mild.
 Antibodies acquired later in life, in the US, only 50% of
adults are seropositive by the age of 50.
 Diagnosis is made by electron microscopy and by PCR.
Other Possible Diarrhoeal
Viruses
Coronaviruses

RNA viruses with a crown-like appearance

Not convincing associated with gastroenteritis at present
Small Round Viruses

Small virus-like particles with a smooth surface, 22-28nm
in diameter

May possibly be parvoviruses, enteroviruses, or cubic
bacteriophages
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Occasionally seen in the faeces of endemic or epidemic
cases of gastroenteritis
Gastrointestinal Viruses
Virus
Genome
Typical disease
incubation Duratio
n
Rotaviruses: dsGroup A, B, segmented
C
RNA
Major cause of
1-3 days
diarrhea in children 24-56 h
5-8 days
3-7 days
Caliciviruses ssRNA
Norwalk
agents
Infects adults and
children
Epidemic viral
gastroenteritis
1-3 days
18-24 h
1-3 days
12-48 h
EAd 40,41
Linear
dsRNA
diarrhea in
children
7-8 days
8-12 d
Astrovirus
+ssRNA
Infects mainly
children and
elderly
1-4 days
1-4 d
问题
 肠道病毒有哪些？是不是肠道感染的所有病毒都称


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为肠道病毒？
简要说明肠道病毒的特性
脊髓灰质炎病毒的传播途径、致病机制是什么？如
何预防脊灰？
B组柯萨奇病毒的致病有何特点？
ECHO病毒、轮状病毒、杯状病毒、小圆结构病毒
分别与哪些疾病有关？