Enteroviruses
Feng-Min Zhang
Microbiol Departman,Harbin Medical University
第 31章 肠道病毒问题
肠道病毒有哪些？是不是肠道感染的所有病毒都称为肠道病毒？
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？
Groups and Serotypes
Picornaviridae（ 小 RNA病毒科 ）
At least 71 serotypes,divided into 4 subgroups
Polioviruses （ 脊髓灰质炎病毒 ）
Coxsackie viruses（ 柯萨奇病毒 ）
Echoviruses（ 埃可病毒 ）
New enteroviruses（ 新肠道病毒 ）
more recently,new enteroviruses subtype have
been allocated sequential numbers (68-71))
Enteroviruses Serotypes
Morphology
27nm,icosahedral symmetry,no envelope
Surface cleft – attachment to cellular receptors:
Immunoglobulin superfamily,integrins,ICAM-1
Enterovirus structure
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-脊髓灰质炎病毒
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
中和试验可分 3个血清型,3型间有部分共同抗原
核酸有 36-52%同源性
人类 是唯一的易感宿主
在猴肾、人胚肾等细胞可增殖，表现为细胞变圆、坏死、脱落等典型溶细胞 CPE
在猴、猩猩等灵长类动物敏感，在神经系统感染，导致肢体麻痹
Transmission
Fecal – oral route (粪－口途径 )
via hands and objects
via food and water
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
Franklin D,Roosevelt
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,
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
免疫性
脊灰病毒感染后可建立牢固特异免疫
以体液免疫为主,在肠道局部产生 sIgA，
阻止病毒入血。血液中出现中和性 IgG、
IgM抗体，阻止病毒进入神经系统。中和抗体可长时间维持（终生）
3型间有部分共同抗原，可以有极弱的交叉保护
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
预防原则
隔离病人
消毒排泄物、饮食卫生、保护水源
流行期不宜做小儿扁挑体摘除手术和其他疫苗接种
疫苗接种,最好的手段
被动免疫：易感者用丙种球蛋白
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
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.
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
- EV leading cause in summer & fall,All types of rash
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
resolution – 1w
Herpangina
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
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.
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,conjunct ivitis - + - -
Respiratory infections + + + +
Undifferentiated fever + + + +
Diabetes/pancreatitis - - + -
Feng-Min Zhang
Microbiol Departman,Harbin Medical University
第 31章 肠道病毒问题
肠道病毒有哪些？是不是肠道感染的所有病毒都称为肠道病毒？
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？
Groups and Serotypes
Picornaviridae（ 小 RNA病毒科 ）
At least 71 serotypes,divided into 4 subgroups
Polioviruses （ 脊髓灰质炎病毒 ）
Coxsackie viruses（ 柯萨奇病毒 ）
Echoviruses（ 埃可病毒 ）
New enteroviruses（ 新肠道病毒 ）
more recently,new enteroviruses subtype have
been allocated sequential numbers (68-71))
Enteroviruses Serotypes
Morphology
27nm,icosahedral symmetry,no envelope
Surface cleft – attachment to cellular receptors:
Immunoglobulin superfamily,integrins,ICAM-1
Enterovirus structure
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-脊髓灰质炎病毒
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
中和试验可分 3个血清型,3型间有部分共同抗原
核酸有 36-52%同源性
人类 是唯一的易感宿主
在猴肾、人胚肾等细胞可增殖，表现为细胞变圆、坏死、脱落等典型溶细胞 CPE
在猴、猩猩等灵长类动物敏感，在神经系统感染，导致肢体麻痹
Transmission
Fecal – oral route (粪－口途径 )
via hands and objects
via food and water
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
Franklin D,Roosevelt
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,
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
免疫性
脊灰病毒感染后可建立牢固特异免疫
以体液免疫为主,在肠道局部产生 sIgA，
阻止病毒入血。血液中出现中和性 IgG、
IgM抗体，阻止病毒进入神经系统。中和抗体可长时间维持（终生）
3型间有部分共同抗原，可以有极弱的交叉保护
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
预防原则
隔离病人
消毒排泄物、饮食卫生、保护水源
流行期不宜做小儿扁挑体摘除手术和其他疫苗接种
疫苗接种,最好的手段
被动免疫：易感者用丙种球蛋白
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
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.
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
- EV leading cause in summer & fall,All types of rash
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
resolution – 1w
Herpangina
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
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.
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,conjunct ivitis - + - -
Respiratory infections + + + +
Undifferentiated fever + + + +
Diabetes/pancreatitis - - + -
