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Chapter Outlines

Chapter 11      Poliovirus and Other Enteroviruses

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11.1 Brief Overview of Enteroviruses Small RNA viruses Naked Picornaviridae family Ubiquitous in nature "Entero" means intestine Transmitted by an oral-fecal route Over 70 distinct types of human enteroviruses 20 recognizable clinical syndromes. See Table 11-1 11.2 The History of Polio Descriptions of poliomyeltitis date to 1500 B.C. Egyptian stele showing "foot drop" (Chapter 1) Significant problem in northern Europe in the late 1800's 1916 NYC, New York, one of the worst epidemics Timeline (Figure 11-1) Polio was a Pubic Concern Disease of mysterious, season appearance. It could paralyze respiratory muscles It had disfiguring, crippling and sometimes fatal results. Era of Cell Culture 1909 Landsteiner and Popper reproduced poliomyelitis in rhesus monkeys. Injected a filtrate of ground-up CNS tissue from a boy that 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. 1949 Advent of cell cultures by Enders, Robbins and Weller: cultivation of polioviruses in non-nervous tissues. Soon began to propagate monkey kidney cells 11.3 Clinical Features of Poliomyelitis Poliomyelitis is rare today because of vaccination efforts. The last cases of poliomyelitis in the U.S. were in 1979 and 2005 (unvaccinated persons from Amish communities) Clinical Features 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. 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 Minor Infections Minor illness followed by: Stiff neck/back, and/or legs occur. These symptoms last 2-10 days followed by a complete recovery. Major illness - Polio Occurs in less than 1% of all poliovirus infections. Flaccid paralysis-weakness Inflammation and sometimes destruction of neurons. Recovery can take up to 2 years and may be incomplete. Weakened muscles. 3 Forms of Major illness Spinal paralysis More common Asymmetric paralysis (occurs on one side) Bulbar Less common Muscle weakness Inability to swallow Patient may require an iron lung or respirator Bulbospinal Combination of spinal and bulbar paralysis Post-Polio Syndrome (PPS) Occurs in a large porportion of individuals who recovered from paralytic poliomyelitis. Occurs 8-71 years post-polio infection (average - 36 years) More common in women than men. Insidious Most common symptoms: New weakness in muscles or limbs involved at the time of acute poliomyelitis Fatigue Pain in the muscles and joints Cause of PPS? Muscle fibers of surviving motor neurons slowly deteriorate over time. Nerve endings eventually destroyed and permanent weakness occurs. Effective management requires an interdisciplinary approach: manage pain, fatigue, anti-inflammatory therapy etc. 11.4 Classification and Structure of Poliovirus Member of the Picornaviridae family Small, 30 nm in diameter Icosahedral-shaped Nonenveloped Acid-stable (+) ssRNA genome ~7441 nucleotides in length 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 (39.2 oF) Inactivation /Disinfection Protocols Chlorine (Bleach) Hydrochloric Acid Aldehydes Heat 50 oC (122 oF) for one hour (in the absence of calcium and magnesium) 11.5 Laboratory Diagnosis of Poliovirus Infections Most common method: isolate virus from stool samples. Grows well in characterized in any human or monkey kidney cell lines (causes good CPEs). Identify serotype with neutralization assays. Nucleic acid methods: genomic sequencing to determine if the infection is caused by vaccine or wild-type virus. 11.6 Cellular Pathogenesis Humans and nonhuman 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 Tonsils How Poliovirus Spreads Through the Bloodstream Major viremia: causes sore throat, headache, fever. Small % of Patients 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 11.7 Viral Replication Polioviruses attach to host cells via the poliovirus receptor (PVR or sometimes CD155). Binding causes a conformational change in the internal capsid protein VP4. Capsid swells, pore is formed, through which the viral + ssRNA genome enters the cytoplasm Uncoating event is not precisely known. Virion RNA serves as an mRNA that is translated into a single, highly autocatalytic polyprotein. Poliovirus Genome 5' end contains a small basic viral protein, VPg. 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. 11.8 Treatment During the Polio Era in the U.S. Drinker respirators or iron lungs introduced in the 1930's Sister Kenny Physical therapy rather than immoblization of the affected muscles Hot packs and hot baths There is no cure. Treatment is supportive care, including physical therapy. No antivirals available. 11.9 Prevention 1950's: monkeys were treated in the nose with picric acid, sodium alum, zinc sulfate The same treatment was tried in humans without promising results. Quickly abandoned this treatment 1952 convalescent serum/passive immunity 1953 gamma globulin - failed to prevent poliovirus infection in humans Inactivated Vaccines Jonas Salk Grew polioviruses in monkey kidney cells, inactivated the viruses with formalin 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. Salk's Inactivated Vaccine (IPV) Licensed in 1955 by the FDA 70% effective in preventing poliovirus infection. 1955 Cutter Episode 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 This did not change the public confidence in the vaccine! Led to new requirements is safety testing of the vaccine. Pharmaceutical GMPs (Good Manufacturing Practices) Surveillance unit set up at the CDC to maintain and scrutinize vaccination programs. 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 (don't need boosters). Sabin's team created an attenuated vaccine by passaging each serotype of poliovirus separately in cynomolgus monkey kidney tissue culture cells. Injected the attenuated strains into the spinal cord of monkeys and the viruses did not revert. Field Trials of Sabin Vaccine Resistance to gain support for another poliovirus vaccine (already have the Salk vaccine which is 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 Poliomyeltitis Research Insitute 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! Live, Attenuated Sabin Vaccine Sabin large field trials in Russia provided confidence that attenuated strains were safe. Within 10 years - two vaccines available against poliovirus! IPV (Salk) and OPV (Sabin) Sabin's vaccine included 3 serotypes. It was administered orally (few drops of liquid). Oral Polio Vaccine (OPV) U.S. CDC Vaccination Recommendation Today No longer use 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 dose @ 4-6 years 11.10 Eradication Efforts 1988 WHO goal - global eradication of poliovirus by the year 2000 Poliovirus eradication considered possible because: 2 vaccines available No animal reservoir 3 attentuated serotypes are stable OPV inexpensive and easy to administer in mass vaccination campaigns Roadblocks to Poliovirus Eradication Poliovirus is contagious - oral-fecal route, stable virus. Use of IPV in tropical regions is problematic. IPV is inefficient in preventing 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)? Progress Towards Poliovirus Eradication Significant progress between 1988 -2003. 2003 Reduced from 125 to 6 polio-endemic countries New pockets of cases in as many as 26 countries that were of polio-free status. WHO intensifying efforts. Educational programs to reinforce the importance and safety of vaccination. 11.11 Other Enteroviruses At least 70 enteroviruses known to infect humans. Some cause myocarditis and dilated cardiomyopathy (DCM). 70% of the general population has been exposed to cardiotropic viruses. About 14-21% of respiratory disease is associated with enterovirus infections. Enterovirus 71 A Re-emerging Viral Pathogen Majority of enterovirus infections are assymptomatic or cause mild or self-limiting infections in children. 4 groups of enteroviruses: Polioviruses Group A Coxsackie viruses Group B Coxsackie viruses Echoviruses First isolated in 1969. Frequent cause of hand, foot, and mouth disease (HFMD) epidemics associated with severe neurological complications in a small % of cases. Significant increase in Enterovirus 71 epidemics in the Asia-Pacific region since 1997.