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Poliovirus



Poliovirus

TEM micrograph of poliovirus virions.
Virus classification
Group: Group IV ((+)ssRNA)
Family: Picornaviridae
Genus: Enterovirus
Type species
Poliovirus

Poliovirus, the causative agent of poliomyelitis, is a human enterovirus and member of the family of Picornaviridae.[1] Poliovirus is composed of a RNA genome and a protein capsid. The genome is single-stranded positive-sense RNA genome that is about 7500 nucleotides long.[2] The viral particle is about 300 Ångström in diameter with icosahedral symmetry. Because of its short genome and its simple composition—only RNA and a non-enveloped icosahedral protein coat that encapsulates it—poliovirus is widely regarded as the simplest significant virus.[3]

Poliovirus was first isolated in 1908 by Karl Landsteiner and Erwin Popper.[4] In 1981, the poliovirus genome was published by two different teams of researchers— by Vincent Racaniello and David Baltimore at MIT[5] and by Naomi Kitamura and others at the State University of New York, Stony Brook.[6] Poliovirus is one of the most well-characterized viruses, and has become a useful model system for understanding the biology of RNA viruses.

Additional recommended knowledge

Contents

Origin and serotypes

There are three serotypes of poliovirus, PV1 (Mahoney or Brunhilde), PV2 (Lansing)[7], and PV3 (Leon); each with a slightly different capsid protein. Capsid proteins define cellular receptor specificity and virus antigenicity. PV1 is the most common form encountered in nature, however all three forms are extremely infectious.[4]

All three forms of poliovirus are structurally similar to other human enteroviruses, coxsackieviruses, echoviruses, and to human rhinoviruses, which also use immunoglobulin-like molecules to recognize and enter host cells.[8] Phylogenetic analysis of the RNA and protein sequences of poliovirus suggests that PV may have evolved from a C-cluster coxsackie A virus ancestor, arising through a mutation within the capsid.[9] The distinct speciation of poliovirus probably occurred as a result of change in cellular receptor specificity from intercellular adhesion molecule-1 (ICAM-1), used by C-cluster coxsackie A viruses, to CD155; leading to a change in pathogenicity, and allowing the virus to infect nervous tissue.

Life cycle

 

Poliovirus infects human cells by binding to an immunoglobulin-like receptor, CD155, (also known as the poliovirus receptor (PVR))[11][8] on the cell surface.[12] Interaction of poliovirus and CD155 facilitates an irreversible conformational change of the viral particle necessary for viral entry.[13][14] The precise mechanism poliovirus uses to enter the host cell has not been firmly established.[15] Attached to the host cell membrane, entry of the viral nucleic acid was thought to occur one of two ways: via the formation of a pore in the plasma membrane through which the RNA is then “injected” into the host cell cytoplasm, or that the virus is taken up by receptor-mediated endocytosis.[16] Recent experimental evidence supports the latter hypothesis and suggests that poliovirus binds to CD155 and is taken up via endocytosis. Immediately after internalization of the particle, the viral RNA is released.[17] However, any mechanism by which poliovirus enters the cell is very inefficient; as an infection is initiated only about 1% of the time.[18]

Poliovirus is a positive stranded RNA virus. Thus the genome enclosed within the viral particle can be used as messenger RNA and immediately translated by the host cell. Upon entry the virus hijacks the cell's translation machinery; causing inhibition of cellular protein synthesis in favor of virus–specific protein production. Unlike most cellular mRNAs the 5' end of poliovirus RNA is extremely long—over 700 nucleotides—and is highly structured. It is this region of the viral genome which directs translation of the viral RNA, and alterations of this region prevent viral protein production. Ultimately it was demonstrated that translation of poliovirus RNA occurs via an internal ribosome entry site (IRES).[19][20][21]

Poliovirus mRNA is translated as one long polypeptide. This polypeptide is then cleaved into approximately 10 individual viral proteins, including:[3][18]  

  • 3Dpol, an RNA dependent RNA polymerase.
  • 2Apro and 3Cpro/3CDpro, proteases which cleave the viral polypeptide.
  • VPg (3B), a small protein that binds viral RNA and is necessary for synthesis of viral positive and negative strand RNA.
  • 2BC, 2B, 2C, 3AB, 3A, 3B proteins which comprise the protein complex needed for virus replication.
  • VP0, VP1, VP2, VP3, VP4 proteins of the viral capsid.

The assembly of new virus particles, (i.e. the packaging of progeny genome into a capsid which can survive outside the host cell) is poorly understood.[16] Fully assembled poliovirus leaves the confines of its host cell 4 to 6 hours following initiation of infection in cultured mammalian cells.[22] The mechanism of viral release from the cell is unclear,[2] but each dying cell can release between 10,000 and 100,000 polio virions.[22]

Pathogenesis

 

The primary determinant of infection for any virus is its ability to enter a cell and produce additional infectious particles. The presence of CD155 is thought to define the animals and tissues that can be infected by poliovirus. CD155 is found only on the cells of humans, higher primates, and Old World monkeys. Poliovirus is however strictly a human pathogen, and does not naturally infect any other species (although chimpanzees and Old World monkeys can be experimentally infected).[23]

Poliovirus is an enterovirus. Infection occurs via the fecal-oral route; meaning that one ingests the virus and it is within the alimentary tract that virus replication occurs.[24] Virus is shed in the feces of infected individuals. In 95% of cases only a primary, transient presence of the virus in the bloodstream occurs (called a viremia) and the poliovirus infection is asymptomatic. In about 5% of cases, the virus spreads, and replicates in other sites such as brown fat, the reticuloendothelial tissues, and muscle. This sustained replication causes a secondary viremia, and leads to the development of minor symptoms such as fever, headache and sore throat.[25] Paraltyic poliomyletis occurs in less than 1% of poliovirus infections. Paralytic disease occurs when the virus enters the central nervous system (CNS) and replicates in motor neurons within the spinal cord, brain stem, or motor cortex, resulting in the selective destruction of motor neurons; leading to either temporary or permanent paralysis and, in rare cases, to respiratory arrest and death. In many respects this neurological phase of infection is thought to be an accidental diversion of the normal gastrointestinal infection.[16]

The mechanisms by which poliovirus enters the CNS are poorly understood. Three theories have been suggested to explain its entry, which are not mutually exclusive, and require that the virus be present in the blood (viremia). One theory is that virus passes directly from the blood into the central nervous system by crossing the blood brain barrier, independent of CD155.[26] A second hypothesis suggests that the virus is transported from the muscle to the spinal cord through nerve pathways by retrograde axonal transport.[27][28] A third hypothesis is that the virus is imported into the CNS by infected monocytes or macrophages.[10]

Poliomyelitis is a disease of the central nervous system. However, CD155 is believed to be present on the surface of most, if not all, human cells and does not explain why poliovirus preferentially infects certain tissues, suggesting that tissue tropism is determined after infection. Recent work has suggested that the type I interferon response (specifically that of interferon alpha and beta) is an important factor that defines which types of cells are infected by poliovirus.[29] In mice expressing CD155 but lacking the type I interferon receptor, poliovirus not only replicates in tissues it normally would not, but these mice are also able to be infected orally with the virus.[30]

Immune system avoidance

Poliovirus uses two key mechanisms to evade the immune system. First, it is capable of surviving the highly acidic conditions of the gastrointestinal tract, allowing the virus to infect the host and spread throughout the body via the lymphatic system.[3] Second, because it can replicate very quickly, the virus overwhelms the host organs before an immune response can be mounted.[5]

Individuals who are exposed to poliovirus, either through infection or by immunization with polio vaccine, develop immunity. In immune individuals, antibodies against poliovirus are present in the tonsils and gastrointestinal tract (specifically IgA antibodies) and are able to block poliovirus replication; IgG and IgM antibodies against poliovirus can prevent the spread of the virus to motor neurons of the central nervous system.[22] Infection with one serotype of poliovirus does not provide immunity against the other serotypes, however second attacks within the same individual are extremely rare.

PVR transgenic mouse

Although humans are the only known natural hosts of poliovirus, monkeys can be experimentally infected and they have long been used to study poliovirus. In 1990-91, a small animal model of poliomyelitis was developed by two laboratories. Mice were engineered to express a human receptor to poliovirus (hPVR).[31][32]

Unlike normal mice, transgenic poliovirus receptor (TgPVR) mice are susceptible to poliovirus injected intravenously or intramuscularly, and when injected directly into the spinal cord or the brain.[33] Upon infection, TgPVR mice show signs of paralysis that resemble those of poliomyelitis in humans and monkeys, and the central nervous systems of paralyzed mice are histocytochemically similar to those of humans and monkeys. This mouse model of human poliovirus infection has proven to be an invaluable tool in understanding poliovirus biology and pathogenicity.[34]

Three distinct types of TgPVR mice have been well studied:[35]

  • In TgPVR1 mice the transgene encoding the human PVR was incorporated into mouse chromosome 4. These mice express the highest levels of the transgene and the highest sensitivity to poliovirus. TgPVR1 mice are susceptible to poliovirus through the intraspinal, intracerebral, intramuscular, and intravenous pathways, but not through the oral route.
  • TgPVR21 mice have incorporated the human PVR at chromosome 13. These mice are less susceptible to poliovirus infection through the intracerebral route, possibly because they express decreased levels of hPVR. TgPVR21 mice have been shown to be susceptible to poliovirus infection through intranasal inoculation, and may be useful as a mucosal infection model.[36]
  • In TgPVR5 mice the human transgene is located on chromosome 12. These mice exhibit the lowest levels of hPVR expression and are the least susceptible to poliovirus infection.

Recently a forth TgPVR mouse model was developed. These "cPVR" mice carry hPVR cDNA, driven by a β-actin promoter, and have proven susceptible to poliovirus through intracerebral, intramuscular, and intranasal routes. In addition, these mice are capable of developing the bulbar form of polio after intranasal inoculation.[36]

The development of the TgPVR mouse has had a profound effect on oral poliovirus vaccine (OPV) production. Previously, monitoring the safety of OPV had to be performed using monkeys, because only primates are susceptible to the virus. In 1999 the World Health Organization approved the use of the TgPVR mouse as an alternative method of assessing the effectiveness of the vaccine against poliovirus type-3. In 2000 the mouse model was approved for tests of vaccines against type-1 and type-2 poliovirus.[37]

Cloning and synthesis

 

In 1981 Racaniello and Baltimore used recombinant DNA technology to generate the first infectious clone of an animal RNA virus, poliovirus. DNA encoding the RNA genome of poliovirus was introduced into cultured mammalian cells and infectious poliovirus was produced.[38] Creation of the infectious clone propelled understanding of poliovirus biology, and has become a standard technology used to study many other viruses.

In 2002 researchers at SUNY Stony Brook succeeded in synthesizing poliovirus from its chemical code, producing the world's first synthetic virus.[39] Scientists first converted poliovirus's published RNA sequence, 7741 bases long, into a DNA sequence, as DNA was easier to synthesize. Short fragments of this DNA sequence were obtained by mail-order, and assembled. The complete viral genome was then assembled by a gene synthesis company. This whole painstaking process took two years. Nineteen markers were incorporated into the synthesized DNA, so that it could be distinguished from natural poliovirus. Enzymes were used to convert the DNA back into RNA, its natural state. The newly minted synthetic virus was injected into PVR transgenic mice, to determine if the synthetic version was able to cause disease. The synthetic virus was able to replicate, infect, and cause paralysis or death in mice. However, the synthetic version was between 1,000 and 10,000 times less lethal than the original virus.[40]

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This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Poliovirus". A list of authors is available in Wikipedia.
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