Enteroviruses

• Genera of the family Picornaviridae


  • Enterovirus
  • Parechovirus
  • Rhinovirus
  • Hepatovirus
  • Aphtovirus
  • Cardiovirus

  
• Structure of Picornaviruses


  • Ss +RNA
  • Virion is icosahedral 22-30nm in diameter
  • Capsid has 60 copies of 4 proteins: VP1, VP2, and VP3 are exposed on the virion surface, VP4 lies buried in close association with the RNA core
  • Immunogenic sites are located on the external parts of the capsid

  
• Unique properties of human Picornaviruses


  • Small nonenveloped viruses
  • They are ether, acidic pH, and detergents resistant (Rhinoviruses are labile at acidic pH)
  • They replicate in the cytoplasm
  • Most viruses are cytolytic
  • Each serotype has a type-specific antigen, which is identifiable by neutralization tests

  
• Reproduction Cycle of Picornaviruses


  (not described in detail)
• Poliovirus was first identified by Karl Landsteiner in 1908 by inoculation of specimens into monkeys. The virus was first grown in cell culture in 1949 which became the basis for vaccines.

  
• Coxsackieviruses were identified in 1948 by inoculation into newborn mice from two children with paralytic disease. These agents were named coxsackieviruses after the town in New York State.
• Echoviruses were identified in 1951 which produced cytopathic changes in cell culture and was nonpathogenic for newborn mice.

  
• More recently, new enterovirus types have been allocated sequential numbers.

  
• Pathogenesis of enteroviruses infections


  1. Routes of transmission: fecal-oral, Saliva, Respiratory droplets, Conjunctival secretions and Skin lesion exudates

  2. Portal of entry: nasopharynx and intestinal mucosa

  3. Replication: in the nasopharyngeal and intestinal epithelium and regional lymph nodes

  4. Spread: by the bloodstream in the reticuloendothelial system and to target organs such as the spinal cord, brain meninges, heart, liver and skin

  5. From the CNS the virus travel via neural pathways to skeletal and heart muscles

  
• There are 3 serotypes of poliovirus (1, 2, and 3) but not common antigen.

  
• Humans are the only susceptible host for poliovirus.

  
• Polio endemic countries (where polio is prevalent)


  • Afghanistan
  • Pakistan
  • Mozambique
  • Democratic Republic of Congo
  • northern Yemen
  • northern Nigeria
  • south-central Somalia

  
• Epidemiology of Polio


  1. Source — human with clinical and subclinical infection

  2. Transmission: primarily via the fecal-oral, by ingesting contaminated food or water

  3. Incubation period - 3 to 35 days, on average — 7-14 days

  4. I.P for nonparalytic symptoms is 3 to 6 days

  5. The onset of paralysis usually occurs 7 to 21 days after infection

  6. Polio is most infectious between 7 - 10 days before and after the appearance of symptoms

  
• Pathogenesis of polio viruses infection

  1. The alimentary phase: Primary replication in the oropharyngeal and intestinal mucosa

  2. The lymphatic phase: Virus spreads to the tonsils and Peyer's patches

  3. The viremic phase: The virus is carried by the bloodstream to various internal organs and regional lymph nodes

  4. The neurologic phase: The virus spreads hematogenously to the spinal cord or brain stem or to both. Damage results in paralysis of the muscles innervated by the affected motor nerves. Paralysis is usually irreversible, and residual paralysis remains for life

  
• Poliomyelitis


  • Inflammation of the gray (polios) anterior matter of the spinal cord (myelos)
  • Death of motor neurons
  • Sensory neurons unaffected
  • The location of motor neurons in the anterior horn cells of the spinal column
• Degeneration of Nerve cells during Acute Polio

  1. Healthy spinal cord

  2. Nerve cell is invaded by poliovirus

  3. One nerve cell has been infected, neighbor has not

  4. Destruction of the infected nerve cells results a lack of nerve supply to the muscles
• Recovery From Acute Paralytic Polio


  1. Surviving motor nerve cells in the brain stem and spinal cord extend new branches to re-connect the nerve cell to the muscle (sprouts)

  2. The new sprouts are now capable of triggering contraction in the muscles and muscle function can be partially or fully regained

  3. Many motor nerve cells end up supplying several times the number of muscle fibers they would normally supply
• Mechanism of Post-Polio Syndrome

  1. New sprouts are unstable

  2. Degenerate over time due to an "overexertion" phenomenon

  3. Resulting once again in muscle fibers that no longer contract, which a survivor recognizes as new weakness and loss of function
• Clinical syndromes associated with polio viruses


  • Inapparent (subclinical) infection(95%)
  • Abortive infections (a minor influenza-like illness).4-5%
  • Aseptic meningitis (1-2%)
  • Encephalitis
  • Paralytic poliomyelitis: spinal poliomyelitis - complete flaccid paralysis of one or more limbs; bulbar poliomyelitis - paralysis of neck and respiratory muscles; bulbospinal poliomyelitis
  • Post-polio syndrome: the virus is no longer present. It may occur many years after the infection (15 - 40 years later) and involves further loss of function in affected muscles (progressive and irreversible damage)as a result of further neuron loss.(non-infectious)

  
• Factors affecting paralysis in poliomyelitis


  • Age less common in infants
  • Trauma [injuries, hypodermic injections, tonsillectomy]
  • Pregnancy [hormonal factors]
  • Immunosuppression: infection with wild-type virus is much more severe in immunosuppressed patients (Vaccine–related paralytic poliomyelitis)

  
• Symptoms of poliomyelitis


  • Early symptoms: High fever, headache, stiffness in the back and neck, asymmetrical weakness of muscles, sensitivity to touch/light, difficulty swallowing, muscle pain, paresthesia (pins and needles),constipation, or difficulty urinating
  • Paralysis: Generally develops 1 - 10 days after early symptoms begin, progresses for 2 - 3 days, and is usually complete by the time the fever breaks
• Egyptian stele from the 18th dynasty showing a victim of polio with a withered leg
• Children with polio sequelae
• Immunity to Polio


  • Active immunity: Life-long, type-specific
  • Local: IgA are present in the tonsils and gastrointestinal tract, and are able to block virus replication
  • Humoral: IgG and IgM can prevent the spread of the virus to motor neurons of the CNS
  • Passive immunity: Maternal antibodies cross the placenta, and protect the infant from polio infection during the first 2-3 months of life

  
• Prevention: good hygiene & vaccinations


  • Intramuscular Poliovirus Vaccine (IPV) Salk: consists of formalin inactivated virus(killed) of all 3 serotypes. Produces serum antibodies only, prevents paralytic poliomyelitis
  • Oral Poliovirus Vaccine (OPV)-Sabin: Consists of live attenuated virus of all 3 serotypes. Produces local immunity through the induction of an IgA response as well as systemic immunity, provides lifelong immunity

  
• Types of polio vaccines

  • Attenuated live vaccine: Live Polio vaccine (LPV), Oral Polio vaccine (OPV) or Sabin vaccine, Trivalent 1, 2, 3
  • Killed or inactivated vaccine (KPV, IPV) or Salk vaccine
  • Recombinant DNA technology. Prevent Reversion to Virulence
  • Passive immunization: Effective Ig vaccination requires administering the vaccine shortly before infection, provides protection for a few weeks, and can prevent paralysis

  
• Comparison of IPV and OPV

  • IPV: Safe, stable, no interference by other viruses, Provide systemic protection IgM/IgG, expensive, difficult administration, required wide vaccine coverage, No detectable IgA in the intestinal tract
  • OPV: cheap, easily administered, excellent herd immunity, provide immediate protection as interferes with wild poliovirus, Production of local IgA, Provide local &systemic protection, Less safe "can cause paralytic polio", less stable specially in tropics, some interference by enteroviruses

  
• Schedule of immunization for polio vaccines

  
• Laboratory diagnosis of polio

  • Recovery of virus: throat swab , rectal swab, stool sample
  • Cell culture: human embryonic fibroblast, monkey kidney cells
  • Identification: by neutralizing test with specific antisera
  • Serology: paired samples, neutralization test against 3 serotype

  
• Clinical syndromes associated with non-polio Enteroviruses


  • Aseptic meningitis, encephalitis and ascending paralysis
  • Common cold syndrome
  • Coxsackie A(1-24): Herpangina (sore throat, fever, vesicles), Hand-foot-and mouth disease
  • Coxsackie B(1-6): Myocarditis, pericarditis, Pleurodynia (Bornholm's disease or Devil's Grippe)
  • ECHO viruses: exanthematous disease (rash)
  • Enterovirus 70: acute hemorrhagic conjunctivitis
  • Enterovirus 71: severe CNS disease
  • Mode of transmission: via fecal-oral / respiratory aerosole

  
• Laboratory diagnosis of enteroviruses infection


  • Culture and isolation of viruses from fecal, pharyngeal, saliva, nasal, skin, conjunctiva, CSF, spinal cord, brain, heart, and blood samples
  • Serology (four-fold or greater rise in neutralizing antibody titer between paired sera or high IgM titers to a single serotype): NT, CFT, IF, ELISA, HAIT
  • RT-PCR

  
• Treatment: No specific antiviral drugs, No vaccine, no passive immunization, Good hygiene is helpful