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Category: Viruses and Viral Pathogenesis
Determinants of Poliovirus Pathogenesis, Page 1 of 2
< Previous page | Next page > /docserver/preview/fulltext/10.1128/9781555817916/9781555812102_Chap29-1.gif /docserver/preview/fulltext/10.1128/9781555817916/9781555812102_Chap29-2.gifAbstract:
This chapter provides a brief synopsis of the natural history of paralytic poliomyelitis, and gives an overview of the status of research concerning the molecular determinants of the pathogenesis of paralytic poliomyelitis. Determinants of the pathogenesis of poliomyelitis are either of viral origin, e.g., non-coding viral sequences, structural or nonstructural viral gene products, or of host origin, e.g., distribution of the cellular receptor and host cell factors required for viral replication. To provide a rational account of the relative contributions of a multitude of factors toward a complex phenomenon, the chapter is subdivided into sections dealing with the main parameters of poliovirus neurological disease. Tropism, neurovirulence, and conditions of the host are discussed separately. The chapter discusses experimental evidence for the genetic basis of neurovirulence in the 5’ non-translated region (5’ NTR) and the coding regions for the structural and nonstructural proteins of poliovirus. Extraneural determinants of neuropathogenicity, such as invasion of or spread within the CNS, combine with intraneural factors, such as IRES-mediated cell type specificity or the efficiency of genome replication. Excellent studies in nonhuman primates in the prevaccine era and recent progress through the advent of genetic engineering and transgenic animal models for human disease have afforded us detailed insight into the pathogenic mechanism of paralytic poliomyelitis.
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Attenuating mutations within the serotype 1 (PV1/LS-c, 2ab) and 3 (PV3/Leon 12a1b) poliovirus strains of Sabin ( 83 ). The general organization of the poliovirus genome is shown below. The positions of the IRES and individual stem-loop domains are indicated by roman numerals atop. Sequence divergence in noncoding regions is indicated by asterisks, mutations in coding regions are shown as vertical bars. PV2 (Sabin) is a naturally occurring attenuated strain whose neurovirulent ancestor is not known. PV1(S) is characterized by a large number of mutations within the coding region P1 for the capsid proteins. Both PV1(S) and PV3(S) feature attenuating mutations within stem-loop V of the IRES.
Attenuating mutations within the serotype 1 (PV1/LS-c, 2ab) and 3 (PV3/Leon 12a1b) poliovirus strains of Sabin ( 83 ). The general organization of the poliovirus genome is shown below. The positions of the IRES and individual stem-loop domains are indicated by roman numerals atop. Sequence divergence in noncoding regions is indicated by asterisks, mutations in coding regions are shown as vertical bars. PV2 (Sabin) is a naturally occurring attenuated strain whose neurovirulent ancestor is not known. PV1(S) is characterized by a large number of mutations within the coding region P1 for the capsid proteins. Both PV1(S) and PV3(S) feature attenuating mutations within stem-loop V of the IRES.
The pathogenic mechanism of provocation poliomyelitis. (A) Anatomical representation of the sciatic nerve dissection procedure. Proximal sciatic nerve dissection severs the connection between the gastrocnemius muscle and the spinal cord by interrupting the supplying peripheral nerve. This blocks the retrograde axonal transport route along the peroneal and sciatic nerves into the CNS. (B) The “localization effect” describes the salient clinical feature of provocation poliomyelitis: localization of initial symptoms of paralysis to the injected limb. CD155 tg mice that are infected with poliovirus by the intravenous route develop paraparesis (simultaneous weakness in both lower extremities) at the onset of clinically overt disease (group I). Trivial skeletal muscle trauma in the form of multiple intramuscular (1M) injections diverts initial neurological symptoms to the lower left extremity, where multiple injections had been administered (group II). Dissection of the sciatic nerve abolishes the localization effect, with >70% of infected animals developing initial paraparesis.
The pathogenic mechanism of provocation poliomyelitis. (A) Anatomical representation of the sciatic nerve dissection procedure. Proximal sciatic nerve dissection severs the connection between the gastrocnemius muscle and the spinal cord by interrupting the supplying peripheral nerve. This blocks the retrograde axonal transport route along the peroneal and sciatic nerves into the CNS. (B) The “localization effect” describes the salient clinical feature of provocation poliomyelitis: localization of initial symptoms of paralysis to the injected limb. CD155 tg mice that are infected with poliovirus by the intravenous route develop paraparesis (simultaneous weakness in both lower extremities) at the onset of clinically overt disease (group I). Trivial skeletal muscle trauma in the form of multiple intramuscular (1M) injections diverts initial neurological symptoms to the lower left extremity, where multiple injections had been administered (group II). Dissection of the sciatic nerve abolishes the localization effect, with >70% of infected animals developing initial paraparesis.
Picornaviruses, their clinical manifestations, and receptor specificities
a ND, not determined; HCAR, human coxsackievirus B and adenovirus receptor; DAF, decay-accelerating factor; ICAM-1, intercellular adhesion molecule 1; LDL, low-density lipoprotein; HAVcr-1, receptor for hepatitis A virus; VCAM-1, vascular cell adhesion molecule 1.
Picornaviruses, their clinical manifestations, and receptor specificities
a ND, not determined; HCAR, human coxsackievirus B and adenovirus receptor; DAF, decay-accelerating factor; ICAM-1, intercellular adhesion molecule 1; LDL, low-density lipoprotein; HAVcr-1, receptor for hepatitis A virus; VCAM-1, vascular cell adhesion molecule 1.
Members of the CD155-related family of genes
a CD155β,γ and mPRR2β are secreted splice variants.
Members of the CD155-related family of genes
a CD155β,γ and mPRR2β are secreted splice variants.