Unit 3 - Polio Virus & Other Enteroviruses Flashcards
Describe a breif overview of Enteroviruses
- Small RNA viruses
- Naked
- Picornaviridae family
- Ubiquitous in nature
- “Entero” means intestine: transmitedd by an oral-fecal route
- Over 70 distinct types of human enteroviruese: 20 recongizable clinical syndromes
What is the history of Polio?
- Descriptions of poliomyelitis date to 1500 bc
- Egyptian stele showing “foot drop”
- Existed quietly for thousands of years as an endemic pathogen
- Significant problem in northern Europe in the 1880s
- Major epidemics largely unknown before the late 19th century
- The 1916 New York City epidemic was one of the worst.
- Poliomyelitis is rare today because of vaccination efforts.
- Last cases of poliomyelitis in the US were in 1979 and 2005
- unvaccinated persons from Amish communities
Why is polio a public health concern?
- Disease of mysterious, seasonal appearance by 1910
- It could paralyze respiratory muscles
- 1 in 1,000 infected children
- 1 in 75 infected adults
- Infection had disfiguring, crippling, and sometimes fatal outcomes
What are the clinical features of Poliomyelitis?
- Portal of entry: mouth
- Person to person spread: oral–fecal route
- Infants appear to be the most efficient transmitters of infection.
- e.g., direct contact with feces when changing diapers or poor sanitary conditions
- Average incubation period: 6–20 days
- Poliovirus may be present in stool for 3–6 weeks and 2 weeks in saliva.
What are the course of Mild infections?
- Variable
- 95% of all poliovirus infections are asymptomatic
- Asymptomatic persons shed virus in stool and are able to transmit the virus to others.
- About 4%–8% of poliovirus infections cause mild symptoms:
- Malaise
- Gastrointestinal distress
- Fever
- Influenza-like illness
- Sore throat
- Complete recovery occurs within a week.
- 1-2% of polio infections are associated with:
- Minor illness followed by stiff neck/back, and/or legs
- These symptoms last 2–10 days followed by a complete recovery
What are the course of Major Illness?
Occurs in less than 1% of all poliovirus infections
- Flaccid paralysis = weakness
- Inflammation and occasional destruction of neurons
- Recovery can take up to two years and may be incomplete.
- Weakened muscles (see Figure 11-3)
What are the Three forms of Major illness?
- Spinal Paralysis
- Bulbar
- Bulbospinal
What is Spinal Paralysis?
- Most common
- Viral invasion of the motor neurons of the anterior horn
- Without nerve stimulation, muscles atrophy and become weak, floppy and poorly controlled, finally becoming completely paralyzed
- Asymmetric paralysis (occurs on one side)
What is Bulbar?
- Less common (2% of cases of paralytic polio)
- Invasion & destruction of nerves within the bulbar region of the brain stem
- Weakening of muscles involved in breathing, speaking, and swallowing
- Patient may require an iron lung or respirator
What is Bulbospinal?
- 19% of all cases of paralytic polio
- Combination of spinal and bulbar paralysis
What is Post-Polio Syndrome? (PPS)
- Occurs in 25-50% of individuals who recovered from childhood paralytic polio
- Insidious; occurs 8–71 years post-polio infection
- Average onset is 36 years post-recovery
- More common in women than men
- Not an infectious process (no viral shedding)
- Most common symptoms:
- New weakness in muscles or limbs involved at the time of acute poliomyelitis
- Extreme fatigue
- Pain in the muscles and joints
What causes PPS?
- Muscle fibers of surviving motor neurons slowly deteriorate over time.
- Nerve endings are eventually destroyed and permanent weakness occurs.
- Effective management requires an interdisciplinary approach
- manage pain, fatigue, anti-inflammatory therapy, etc.
What is the classicfication and Structure of Poliovirus?
- Member of the Picornaviridae family
- Small, 30 nm in diameter
- Icosahedral-shaped
- Non-enveloped
- Acid-stable
- (+) ssRNA genome ~7441 nucleotides in length
What is the stability of enteroviruses in the Environment?
Resistant to:
- pH levels less than 3 (stomach acid)
- Digestion by most proteases
- Detergents
- 70% alcohol
- Solvents (e.g., ether and chloroform)
- Disinfectants (e.g., 5% Lysol, 1% QUATS)
- May be stable several days to several weeks at 4oC (39.2oF)
What are the inactivation/Disinfection Protocols?
- Chlorine bleach
- Hydrochloric acid
- Aldehydes
- Heat 50oC (122oF) for one hour (in the absence of calcium and magnesium)
What are the Laboratory Diagnosis of Poliovirus Infections?
- Most common method: isolate virus from stool samples or swab of the pharynx
- Grows well in characterized in any human or monkey kidney cell lines (causes good CPEs)
- Identify serotype with neutralization assays
- Nucleic acid methods: PCR and sequencing used to determine if the infection is caused by “wild-type” virus (encountered in nature) or “vaccine” virus
What is the cellular Pathogenesis?
- Humans and non-human primates are the only known natural hosts of polioviruses.
- Does not infect other experimental animals (e.g., mice)
- Likely due to the lack of poliovirus receptor
- Once ingested, polioviruses invade two lymphoid tissues:
- Peyer’s patches (aggregations of lymphoid tissue on small intestine)
- Tonsils
How does Poliovirus Spread through the bloodstream?
- Major viremia: flu-like symptoms; sore throat; headache; fever
- Penetration of the CNS appears to be incidental & provides no known benefit to the virus
What is the small percent of patients who have poliovirus?
- Polioviruses carried via the bloodstream to the anterior horn cells of the spinal cord
Results in lesions in the spinal cord and brain
- Motor neuron destruction
- Paralysis
- Respiratory arrest
- Death
What is the Viral Replication of Polioviruses?
- Polioviruses attach to host cells via the poliovirus receptor (PVR; also called CD155).
- Binding causes a conformational change in the internal capsid protein VP4.
- Capsid swells and a pore is formed, through which the viral + ssRNA genome is “injected” into the cytoplasm
- Uncoating event is not precisely known
- Receptor-mediated endocytosis may also occur
- Virion RNA serves as an mRNA that is translated into a single, highly autocatalytic polyprotein.
Polio Entry
Describe the Poliovirus Genome
- 5′ end contains a small basic viral protein (VPg)
- primer for RNA synthesis; new (-) ssRNA serves as template for new (+) ssRNA
- 5′ end also contains a cloverleaf or tRNA-like structure that serves as an internal ribosomal entry site (IRES).
- The 3′ end of the genome is polyadenylated.
What is involved in the treatment of Poliomyelistis?
- During the Polio era in the United States:
Drinker respirators (“iron lungs”) introduced in the 1930s
- Sister Kenny:
Physical therapy rather than immobilization of the affected muscles
Hot packs and hot baths
Success was controversial
Foundation for modern physical therapy
- There is no cure.
Treatment is supportive care, including physical therapy.
No antivirals are available.
What is the Iron Lung/Drinker Respirator?
- Negative pressure ventailator
- Pumps controlling airflow periodically decrease and increase the air pressure within the chamber and on the chest it cause lungs to fill and expel.
What famous president had Polio?
Franklin Delano Roosevelt
- 32nd president of the United States; contracted “polio” at age 39 (Guillain-Barre Syndrome?)
- Roosevelt went to Warm Springs Georgia in the 1920s in hopes that the warm water would improve his polio-induced paraplegia
- constant visitor for 2 decades; died there in 1945
- Roosevelt Warm Springs Institute for Rehabilitation
What was the March of Dimes?
- The March of Dimes was established by FDR to fight polio.
- The mission focus was shifted to premature birth and birth defects.
- Sabin and Salk received grant funds for their research.
What do you prevent Poliomyelistis?
- In 1909 Landsteiner and Popper reproduced poliomyelitis in rhesus monkeys.
- Injected a filtrate of ground-up CNS tissue from a boy who had died of polio into the peritoneum of the monkeys.
- For the next 40 years, research was limited because animals (monkeys) were needed to do the research.
Ways of Prevention Continued:
- 1949: Advent of cell cultures by Enders, Robbins, and Weller
=Cultivation of polioviruses in non-nervous tissues
=Soon began to propagate monkey kidney cells
- 1950s: Monkeys were treated in the nose with picric acid, sodium alum, zinc sulfate
=Same treatment tried in humans without promising results
=Quickly abandoned this treatment
- 1950: Hammon showed experimentally that passive immunization could halt infection and reduce disease severity
- 1953: Gamma globulin failed to prevent poliovirus infection in humans
What is involved in the Inactivated Vaccines?
- Jonas Salk
=Grew polioviruses in monkey kidney cells
=Inactivated the viruses with formalinlb
=Albert Milzer took a similar approach but used UV to inactivate polioviruses.
- By 1953, preliminary tests of Salk’s inactivated vaccine on children and adolescent volunteers were favorable.
- Mass vaccination trials using Salk’s inactivated vaccine began.
What is Salk’s Inactivated Vaccine (IPV)?
- Licensed in 1955 by the FDA
- 70% effective in preventing poliovirus infection
What is the Cutter Vaccine Episode? (1955)
- Cutter, manufacturer of the Salk vaccine, produced vaccine that was inadequately inactivated.
- 260 cases of vaccine-related poliomyelitis
- 126 cases through family contacts
- 94 cases from vaccination
- 40 cases by community contacts
- Did not change the public confidence in the vaccine.
- Led to new requirements for safety testing of the vaccine
- Pharmaceutical GMPs (good manufacturing practices)
- Surveillance unit set up at the CDC to maintain and scrutinize vaccination programs
What are the live, attenuated poliovirus Vaccines?
- Developed by Albert Sabin
- More appealing because it was believed that an active infection came closest to producing the natural situation
- Attenuated strains should produce longer-lasting immunity (no need for booster immunizations).
- Major concern: Would attenuated strains revert to wild-type?
What was involved in the attenuation of Poliovirus strains for vaccine development?
- Monkey testicular cells or intracerebral passages in rhesus monkeys
- Passaged by feeding chimpanzees and collecting excreted strains
- Cynomolgus monkey kidney tissue culture cells (MKTC cells)
- SV40 virus contamination
What was the Sabin Strain Attenuation/Passaging Process?
- Attenuation process “weakened” virus by introducing mutation in IRES region
Three Strains:
- Sabin Type 1 - Strain Mahoney 1
- Sabin Type 2- Strain P712
- Sabin Type 3 - Strain Leon III
What are the field trials of the Sabin Vaccine?
- Difficult to gain support for trials of another poliovirus vaccine
- Already had the Salk vaccine that was 70% effective
- 1958: First large scale field trial
- 200,000 children in Singapore vaccinated with an attenuated Sabin serotype 2 poliovirus vaccine
- Same year (1958) Professor Mikhail Petrovich Chumakov, Director of the Poliomyelitis Research Institute in Moscow, manufactured more virus using seed strains from Sabin
- 15 million Russians vaccinated in just over a year with no untoward effects
- By 1960, 100 million Russians vaccinated with no untoward effects
What else is involved in the Live, Attenuated Sabin Vaccine?
- Large field trials in Russia provided confidence that Sabin’s attenuated strains were safe.
- Within 10 years, two vaccines were available against poliovirus.
- IPV (Salk) and OPV (Sabin)
- Sabin’s vaccine included three serotypes.
- It was administered orally (few drops of liquid).
- Oral polio vaccine (OPV)
What is the U.S. CDS’s Vaccination Recommendation today?
- No longer use of OPV to avoid vaccine-associated paralytic polio (VAPP)
- Children get:
4 doses of IPV @ 2 months
4 doses of IPV @ 4 months
1 dose of IPV @ 6–18 months
1 booster IPV dose @ 4–6 years
What were the eradicatino efforts?
- 1988 WHO goal: global eradication of poliovirus by the year 2000
- Poliovirus eradication considered possible because:
Two vaccines are available.
No animal reservoir
Three attenuated serotypes are stable.
OPV is inexpensive and easy to administer in mass vaccination campaigns.
What are the roadblocks to poliovirus Eradication?
- Poliovirus is a contagious (oral–fecal route) and stable virus.
- Use of IPV in tropical regions is problematic.
- IPV is inefficient in preventing the spread of virus.
- Some resistance to mass vaccination
- How can we tell if the vaccine is successful?
- only 1 out of 100 people suffer from the paralytic polio
What is the progress towards poliovirus eradication?
- Significant progress between 1988 and 2003
- 2003 reduced from 125 to 6 polio-endemic countries
- New pockets of cases in as many as 26 countries that had been polio-free
- WHO intensifying efforts
- Educational programs to reinforce the importance and safety of vaccination
What was involved in the Endemic Polio?
Endemic polio viruses eliminated from all but 3 countries in the world (Nigeria, Pakistan, and Afghanistan); India removed in February 2012
What was the Final Inch (2009)?
- Documentary focusing on the ongoing efforts to eradicate polio in India, Pakistan, and Afghanistan
- Funded in part by Google to promote public awareness about polio and the efforts of public health workers.
- “National Immunization Day” in slum areas of India and Pakistan in April 2007
What is the endemic Polio in Nigeria?
- Polio infection rates have skyrocketed nearly 800% in Nigeria in 2009
121 cases in 2012 and 4 cases in 2013
- Immunization program temporarily shut down in 2003 because safety questions about the polio vaccine arose
- Nigeria, along with several other poor nations, uses an oral polio vaccine (OPV)
more affordable, more accessible, and can protect entire villages
Live-attenuated; causes polio at a rate of 2-4 cases per million
- Both socio-political and cultural beliefs lent to a unfavorable perception of the vaccine
“Polio vaccine was contaminated with antifertility drugs so that young Muslim girls would be unable to reproduce”
- 10 volunteer polio vaccinators killed in February 2013; 9 female polio workers killed in Pakistan in December 2012
setback to progress on the polio campaign in the region
What are some other enteroviruses?
- At least 70 enteroviruses are known to infect humans.
- The majority of enterovirus infections are asymptomatic or cause mild or self-limiting infections in children.
- Four groups of enteroviruses:
- Polioviruses
Non-polio
- Group A Coxsackie viruses
- Group B Coxsackie viruses
- Echoviruses
What else is involved with Enteroviruses?
- Some cause myocarditis and dilated cardiomyopathy (DCM)
- Inflammation of the myocardium
- Enlarged heart; congestive heart failure
- 50% mortality rate with DCM
- 70% of the general population has been exposed to cardiotropic viruses
- ½ experience acute viral myocarditis
- About 14%–21% of respiratory disease is associated with enterovirus infections
- Mild, self-limiting disease
What is Coxsackie Virueses?
- Discovered in 1948-49 by NYS DOH scientist Gilbert Dalldorf
===Work done in monkeys suggested that fluid collected from a non-polio virus preparation could protect against the crippling effects of polio
===Attempted to isolate protective viruses from the feces of polio patients ( 1st in Coxsackie, NY)
- Cause a variety of infections and were subdivided into groups A and B based on their pathology in newborn mice
What are Group A and Group B involved in Coxsackie Viruses?
Group A
- Infect skin and mucous membranes
- Cause mouth sores, acute hemorrhagic conjunctivitis, and hand, foot and mouth (HFM) disease
- Nonspecific febrile illnesses, rashes, upper respiratory tract disease, and aseptic meningitis
- Causes paralysis and death in mice
Group B
- Infect the heart, pleura, pancreas, and liver
- Cause pleurodynia, myocarditis, pericarditis, and hepatitis
- Pericardial effusion (“fluid around the heart”)
- Development of insulin-dependent diabetes (IDDM)
What is Hand, Foot and Mouth Disease?
- Affects infants and children (nursery school epidemics)
- Moderately contagious and is spread through direct contact with the mucus, saliva, or feces of an infected person
- 3-7 day incubation period
- Fever, painful sores may appear in the mouth and/or throat
- Rash may become evident on the hands, feet, mouth, tongue
- No specific treatment
