PoliomyelitisHarish Jairam10-13-2003

HistoryAssociated with man since ancient timesEgyptian hieroglyph indicates presence since 1400 BC1840 - Heinle characterizes poliomyelitisPoliomyelitis grey marrow in Greek1954 - Salk vaccine1960 - Sabin vaccine1991 Molla produces polio in vitro from virus RNA2002 completele synthetic production

StructureSmall; 28 30 nm in diameterStructure is intersection of icosahedron and dodecahedron3 external capsid proteins (VP1, VP2, and VP3) with conserved antiparallel beta barrel coresCapsid structural stability extremely temperature sensitiveB C loop of VP1 important for antigenic siteSequence canyon formed between proteins important for immunological reasons and receptor binding

Structure

Cell Binding and EntryBinds only to poliovirus receptor (Pvr)Pvr is a transmembrane glycoprotein with three extracellular immunoglobulin like domainsPvr is involved with actin skeletonPoor viral entry probability ( 0.1 - 1%)

Cell Binding and Entry

Poliovirus GenomeSingle RNA molecule ~7500 nucleotides3 sub-regions with 10 protein productsIRES important for virulence

Anti-Host ActivityShuts off host transcription2B, 2BC, and 3A interfere with apoptotic pathways3A causes tumor necrosis receptor depletion, making cell resistant to TNF necrosis2BC, 3A interfere with antiviral cytokine secretionMany transcription factors bound rather than proteolysedIncreases cell membrane lipid composition, leads to membrane rupture5 UTR determines if the virus will by lytic or nonlytic

RNA ReplicationRNA polymerase (3D)RNA is copied into RNA template for further RNA replication; no free -RNA50:1 ratio +RNA: -RNAVpg is used as primer for both + RNA synthesis and RNA synthesisQuality control proteins to maintain only intact RNA is used for replicationMutation prone synthesis, ~1 mutation/ replication

PathogenesisSymptoms of poliomyelitis always CNS specificNeurological symptoms found in 1-2% of infected individualsThree possible routes of entry into CNSRetrograde axonal transportTransport across blood brain barrierTransport via infected macrophages (Trojan Horse)Specific to CD155 (Pvr) receptorTropic to lower spinal cord and alimentary tract5 NTR key to neurovirulence, especially IRESVirus with rhinovirus analogue IRES fails to propagate in neuronal cellsProvocation Poliomyelitis

SerotypesSpecificity to receptor restricts mutation rate; slow genetic driftOccur because of immunological reasons, vary at sequence canyonThree serotypes with no cross immunityType 1 polio90%Weakest, only 1% causes neuroparalysisType 2 polio9% (Eliminated)Type 3 polio1%Greater temperature stabilityRequires trivalent polio vaccinePolioviruses can also vary in phenotype of virulence, host cell lysis, and ability to raise host defense triggers

VaccinesSalk or Inactivated Polio Vaccine (IPV) 1954Formalin killed virusBalance between killing virus and antigenicity (Cutter Incident)Difficult to produce in mass quantitiesDoes not work in tropical climates because of interference from other entric virusesSabin or Oral Polio Vaccine (OPV) 1960Alters IRES functionReduces virus efficiency, replication rate, neuronal invasionRisk of reversion to more virulent form through mutation1 in 1.2 million vaccinations produces neuronal effects

EradicationHistorically, 0.5% of population became paralyzed by poliomyelitisEasily transmissible, less than 1% clinically recognizable1988 World Health Assembly calls for global polio eradication by 2000Brazils innovative immunization campaignsFailures of smallpox eradication campaignThreat of bioterrorism, remaining Laboratory strains, synthetis productionVaccine-driven poliovirus (VDPV) in Egypt, HispaniolaElimination of Serotype 2

Decline in Poliomyelitis

World Polio Map

World Polio Map

World Polio Map

Resources

Semler, Bert L.; Wimmer, Eckard; Molecular Biology of Picornaviruses; ASM Press: Washington, 2002Koch, Friedrich; Koch, Gehhard; The Molecular Biology of Poliovirus; Springer Verlag: New York, 1985Semler, Bert L.; Ehrenfeld, Ellie; Molecular Aspects of Picornavirus Infection and Detection; ASM Press: Washington, 1988Daniel, Thomas M;Robins, Frederick C.; Polio; University of Rochester Press: Rochester, 1997