Route of poliovirus infection in host
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Poliovirus enters the human body either through the nose or mouth, then proceeds into the digestive tract. If the virus survives the harsh conditions of the stomach, it can infect the cells lining the intestine: the gut mucosa. In the gut mucosa, the virus infects cells and replicates. While the exact mechanism of infection remains uncertain, Peyer's Patches, which are nodules consisting of thirty to forty organized lymphoid follicles in the submucosal layer of the intestinal lining, have been implicated in this process.
In 1% of infections, the virus spreads from the intestine into the blood and central nervous system(CNS). The virus may migrate from the Peyer's patches to the bloodstream, from which the nervous system is accessible. Another proposed means of entering the nervous system is that the virus travels directly through the nerves rather than through the blood. Once the virus has entered the central nervous system, its replication in motor neurons of the anterior horn and brain stem can result in cell destruction and causes the typical clinical manifestations of paralytic poliomyelitis.
The Neuron
Source:http://weber.u.washington.edu~chudler/chmodel.html
Replication of poliovirus
1. Attachment/ Absorption: The capsid of poliovirus is composed of an icosahedral arrangement of 60 protomers, each containing polypeptides VP1, VP2, VP3, and VP4, which were all derived from cleavage of original protomer VP0. The virus binds to the host cell receptor, requiring interaction of the viral binding site with the host cell receptor.
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The specific binding site on poliovirus involves VP1, VP2 and VP3 which interact with host cell receptor CD155, an immunoglobulin-like molecule with 3 domains. Viral attachment involves 'dual tropism'; the virus infects primate cells of two distinct cell types: lymphoid and epithelial cells in the gut and neurons in the CNS.
2. Penetration/ Uptake: Viral RNA is released into the cytoplasm of the host cell through a membrane chanel.
3. Uncoating: Virus undergoes conformational changes upon attachment due to the loss of VP4, thus its integrity is destroyed, and it is no longer infective; however, 1 out of every 200 virus particles is able to successfully transport its RNA into the cytoplasm quickly enough where it can commence synthesis of macromolecules of new virions.
4. "Shut-off" of host cell macromolecular synthesis: Host cell protein synthesis and RNA synthesis are inhibited. This is due to cleavage of the cap-binding complex (CBC) that is required of all eukaryotic mRNA's during initiation of translation. This process serves a dual function: to free up more ribosomes to translate the viral genomes, and second, to ensure that the cell will break down and die, ultimately releasing the newly assembled viral particles. This is initiated at approximately 1/2 hour after infection, and within 2 hours, a sharp decrease in cellular macromolecular synthesis can be observed.
5. Synthesis of viral components: Poliovirus is a positive- sense single stranded RNA virus, meaning the RNA is of the same polarity, or sense, as mRNA. Thus, viral RNA is able to code for all the proteins needed during replication and it is infectious itself. The central player in replication of RNA viruses is the viral RNA-dependent RNA polymerase. The 53 kDa poliovirus polymers, together with other viral and possibly host proteins, carry out viral replication in the host cell cytoplasm. Synthesis is initiated approximately 2.5 to 3 hours after infection takes place. This process involves protein synthesis, protein processing, and RNA replication of the viral genome:
| Protein Synthesis | · Viral
RNA binds to host cell ribosomes · Acting like mRNA, viral RNA is translated in its entirety into one large polypeptide· The polypeptide is cleaved into RNA polymerase, protease enzymes and new capsid proteins |
| Protein Processing | ·
Proteases breakdown the large polypeptide into its components parts · "Shut-off" occurs via a protease |
| RNA Replication | · RNA
polymerase synthesizes (-)-strand RNA (a strand complimentary to the RNA template) · When ready, (-)-strand RNA is used as templates to make a (+)- sense copy of the original genome· Double stranded RNA (called replicative intermediates composed of both (+)- strand and smaller (-) -stranded RNA) are formed· New genome formation sends messages to the cell's translation machinery, leading to a high level of viral protein production |
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6. Assembly: The newly synthesized RNA is packaged inside a capsid. Viral particles are assembled through morphogenesis, and proteolytic cleavage of the capsid protein forms the final particle: a P1 polyprotein precursor is cleaved into a protomer composed of VP0, 1, and 3, which unite together and envelop the viral RNA. Assemblage occurs 4-6 hours after infection.
7. Maturation: Maturation of the virus involves cleavage of VP0 into VP2 and VP4.
8. Release: Particles are then released from the host cell via cell lysis. This is most likely due to a 'preprogrammed' event which takes place after a particular time after "shut-off" of host cell protein synthesis and RNA synthesis. The free viral particles are now allowed to infect other host cells. Migration to the nerve tissue will result in the characteristic pathology of paralytic poliomyelitis. Cell lysis takes place approximately 6-10 hours after infection.
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