1、,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 subgrou
2、ps 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 recept
3、ors: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VP1VP4四种蛋白，VP1VP3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
4、 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 objectsvia food and water,Perhaps th
5、e 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 si
6、te-he attended Harvard University and Columbia Law School. On St. Patricks 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 w
7、on 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 foug
8、ht 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 t
9、erms.,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,
10、 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,Laborato
11、ry 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
12、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
13、 (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
14、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 i
15、ts 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.
16、 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 age
17、nts 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 cap
18、acity 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
19、 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 on
20、e 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 assoc
21、iated 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 co
22、mpletely 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 gr
23、oup 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
24、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
25、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 Coxs
26、ackie 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 diseas
27、e,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 ws no gingiv
28、itis,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.
29、 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
30、 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 immunocompro
31、mised 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 coxsac
32、kie 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
33、 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 betwee
34、n 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 ambiguitie
35、s 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. Ent
36、erovirus 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,
