Enteroviruses

Genera of Picornaviruses Enterovirus Polio Coxsackie A and B Echo Other enteroviruses Diseases of the human (and other) alimentary tract (e.g. polio virus) Rhinovirus Disease of the nasopharyngeal region (e.g. common cold virus) Cardiovirus Murine encephalomyocarditis, Theiler's murine encephalomyelitis virus Aphthovirus Foot and mouth disease in cloven footed animals Hepatovirus Human hepatitis virus A Others Drosophila C virus, equine rhinoviruses, cricket paralysis virus

Categories of Enteroviruses Viral meningitis, rash,ARD 4 types(68-71) Other Enteroviruses Viral meningitis, with orchitis 32 types Echioviruses Viral meningitis, but no orchitis 6 types (B1-B6) Coxsackie B viruses Viral meningitis plus, rash, ARD, myocarditis, orchitis 23 types ( A1-A22, A24) Coxsackie A viruses Asymptomatic infection, viral meningitis, paraalytic disease, poliomyelitis 3 types Polioviruses Clinical Diseases Serotypes Virus

Properties of enteroviruses Property Enteroviruses Size (nm) Capsid form Polypeptide RNA type RNA molecular weight Acid Optimal temperature for growth(oC) Density in caesium chloride (g/m) 22-30 Icosahedral VP1, VP2, VP3, VP4 SS-PS 2000,000-2600,000 Stable* 37 1.34*

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 of enterovirus infection Replication in oropharynx Rhino,echo, coxsackie,polio Primary viremia Secondary viremia Target Tissue Skin Muscle Brain Meninges Liver Echo Coxsackie A Echo Coxsackie A, B Polio Coxsackie Echo Polio Coxsackie Echo Coxsackie

Pathogenicity(1) ASYMPTOMATIC All enteroviruses PARALYSIS - permanent Polio 1, 2, 3 Coxsackie A7 PARALYSIS - temporary Coxsackie B1-6 MENINGITIS (aseptic) Echo, Coxsackie A and B Polio, Entero 71 ENCEPHALITIS Entero 71 Polio, Echo

Pathogenicity(2) RASH - macular Many enteroviruses - vesicular - (e.g. 'Hand Foot Mouth') Coxsackie A SUMMER FEBRILE ILLNESS Many enteroviruses VESICULAR PHARYNGITIS ('Herpangina') Coxsackie A MYOCARDITIS Coxsackie B

Pathogenicity(3) EPIDEMIC MYALGIA ('Bornholm') Coxsackie B UPPER RESPIRATORY INFECTION (cold) Echo, Coxsackie A PANCREATITIS Coxsackie B GASTRO-ENTERITIS Many enteroviusess CONJUNCTIVITIS (Haemorrhagic) Entero 70 HEPATITIS Entero 72 (hepatitis A virus)

Human diseases caused by enteroviruses Polio Cox A Cox B Echo Other Asymptomatic infection Yes Meningitis(脑膜炎) Paralysis(麻痹,瘫痪) No Febrile exanthems(热疹） Acute respiratory disease Myocarditis(心肌炎) Orchitis(睾丸炎

Immunity Antibody is the major protective immune response to the enteroviruses . Secretory antibody can prevent the initial establishment of infection in the oropharynx and gastrointestinal tract, and serum antibody prevents viremic spread to the target tissue and therefore disease. Cell-mediated immunity is not usually involved in protection but may play a role in pathogenesis.

Laboratory Diagnosis Culture Serology Genome

Poliovirus

Important Characteristics

Important Characteristics D or N antigen: Type specific (CFA) C or H antigen: Common antigen (CFA) Type 1-3

Pathogenesis Source of infection: Apparent and subclinical patients Incubation: 7-14 days Pathogenesis: Only much less than 0.1% subjects exposed to polio virus form the flaccid paralysis

Clinical Syndromes Asymptomatic illness: 90% Abortive poliomyelitis, the minor illness: 5% infected people Nonparalytic poliomyelitis or aseptic meningitis: 1%-2% of patients with poliovirus infections. Paralytic polio, the major illness: 0.1% to 2%of persons with poliovirus

Victims of paralytic polio

Child with polio sequelae

Paralyzed child in an iron lung

Iron lung ward in the 1950's

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.

Immunity sIgA and neutralizing antibody (IgG, IgA, IgM) persist for life span

Lab Diagnosis Cell culture involves fibroblastic MRC-5 cells 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

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

Advantages and disadvantages of opv 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 Disadvantages Risk 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 Effectiveness Good stability during transport and in storage Safe administration in immunodeficient patients No risk of vaccine-related disease Disadvantages Lack of induction of local (gut) immunity Need for booster vacine for lifelong immunity Fact that injection is more painful than oral administration Fact that higher cominity immunization levels are needed than with live vaccine

Cases per 100,000 population United States Reported cases per 100000 population 100 10 1 0.1 0.001 0.01 1950 1960 1970 1980 1990 Inactivated (Salk) vaccine Oral vaccine Cases per 100,000 population United States

Total cases Sweden and Finland 10000 Killed (Salk) vaccine 1000 Reported cases 100 10 1 1950 1955 1960 1965 1970 1975

Reciprocal virus antibody titer 512 128 32 8 2 1 Serum IgG Serum IgM Nasal and duodenal IgA Nasal IgA Serum IgA Duodenal IgA Days Vaccination 48 96 Killed (Salk) Vaccine Live (Sabin) Vaccine

Coxsackie Virus

Features of coxsackievirus infection in the labortory Types Growth in MK Effect in cell culture sucking mice Coxsackie A virus 1-24 a + Paralysis Coxsackie B virus 1-6 + Spasticity MK , monkey kidney a Coxsackievirus A23 now classified as echovirus 9

Features of coxsackievirus infection in man Coxsackievirus A 1-24 Asptic meningitis Febrile illness Herpangina疱疹性咽峡炎 Hand-foot-and-mouth disease Coxsackievirus B 1-6 Neonatal disease Myocarditis, hepatitis Meningitis

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疱疹性咽峡炎- caused by group A coxsackieviruses. Epidemic Pleurodynia胸膜痛(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胰腺炎/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 疱疹性咽峡炎 Herpangina – usually coxackie A acute onset, fever, sore throat, dysphagia lesions – posterior pharynx can persist w’s no gingivitis

ECHO virus

Important Characteristics Not produce diseases in sucking mice, rabbits, or monkeys; Cause aseptic meningitis, infantile diarrhea, Monkey kidney and human embryonated kidney cell culture

Clinical syndromes associated with echoviruses Main syndromes Aseptic meningitis Paralysis Rash Respiratory disease Other features Pericarditis心包炎and myocarditis Neonatal infection

Illness associated with recently identified enteroviruses Enterovirus 68 Pneumonia and bronchiolitis Enterovirus 69 Isolated from an ill person in Mexico Enterovirus 70 Acute hameorrhagic conjunctivitis Enterovirus 70, 71 Paralysis, meningo-encephalitis Enterovirus 71 hand-foot-and-mouth disease Enterovirus 72 Hepatovirus( Hepatitis A)