Poliovirus
Encyclopedia
Poliovirus, the causative agent of poliomyelitis
, is a human enterovirus
and member of the family of Picornaviridae.
Poliovirus is composed of an RNA
genome
and a protein
capsid. The genome is a single-stranded positive-sense
RNA genome that is about 7500 nucleotide
s long. The viral particle is about 30 nanometre
s 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.
Poliovirus was first isolated in 1909 by Karl Landsteiner
and Erwin Popper
. In 1981, the poliovirus genome was published by two different teams of researchers— by Vincent Racaniello
and David Baltimore
at MIT
and by Naomi Kitamura and others at the State University of New York, Stony Brook. Poliovirus is one of the most well-characterized viruses, and has become a useful model system for understanding the biology of RNA viruses.
Poliovirus infects human cells by binding to an immunoglobulin-like receptor, CD155
, (also known as the poliovirus receptor (PVR)) on the cell surface. Interaction of poliovirus and CD155 facilitates an irreversible conformational change of the viral particle necessary for viral entry. The precise mechanism poliovirus uses to enter the host
cell has not been firmly established. 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
. 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. However, any mechanism by which poliovirus enters the cell is very inefficient; as an infection is initiated only about 1% of the time.
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. On entry the virus hijacks the cell's translation machinery; causing inhibition of cellular protein synthesis in favor of virus–specific protein production. Unlike the host cell's mRNAs the 5' end
of poliovirus RNA is extremely long—over 700 nucleotides—and is highly structured. This region of the viral genome is called internal ribosome entry site
(IRES) and it directs translation of the viral RNA. Genetic mutations in this region prevent viral protein production.
Poliovirus mRNA is translated as one long polypeptide. This polypeptide is then auto-cleaved by internal proteases into approximately 10 individual viral proteins, including:
The assembly of new virus particles, (i.e. the packaging of progeny genome into a capsid which can survive outside the host cell) is not fully understood. Fully assembled poliovirus leaves the confines of its host cell 4 to 6 hours following initiation of infection in cultured mammalian cells. The mechanism of viral release from the cell is unclear, but each dying cell can release up to 10,000 polio virions.
es and echovirus
es), as well as to human rhinovirus
es, which also use immunoglobulin-like molecules to recognize and enter host cells. Phylogenetic analysis of the RNA and protein sequences of poliovirus (PV) suggests that PV may have evolved from a C-cluster coxsackie A virus
ancestor
, that arose through a mutation within the capsid. 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.
The mutation rate in the virus is relatively high even for an RNA virus with a synonymous substitution rate of 1.0 x 10-2 substitutions/site/year and
non synomymous subtitution rate of 3.0 x 10-4 substitutions/site/year. Base distribution within the genome is non random with adenosine being less common than expected at the 5' end and higher at the 3' end. Codon use is non random with codons ending in adenosine being favourec and those ending in cytosine
or guanine
being avoided. Codon use differs between the three genotypes and appears to be driven by mutation rather than selection.
There are three serotype
s of poliovirus, PV1, PV2 , and PV3; 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
. Wild polioviruses can be found in approximately 10 countries. PV1 is highly localized to regions in India, Pakistan, Afghanistan, and Egypt, but following outbreaks of poliomeyletis in 2003–2004 it remains widespread in West and Central Africa. Wild poliovirus type 2 has probably been eradicated; it was last detected in October 1999 in Uttar Pradesh
, India. Wild PV3 is found in parts of only five countries (Nigeria, Niger, Pakistan, India, and Sudan).
Specific strains of each serotype are used to prepare vaccines against polio
. Inactive polio vaccine (IPV) is prepared by formalin inactivation of three wild, virulent reference strains, Mahoney or Brunenders (PV1), MEF-1/Lansing (PV2), and Saukett/Leon (PV3). Oral polio vaccine (OPV) contains live attenuated (weakened) strains of the three serotypes of poliovirus. Passaging the virus strains in monkey kidney epithelial cells introduces mutations in the viral IRES, and hinders (or attenuates) the ability of the virus to infect nervous tissue.
Polioviruses were formerly classified as a distinct species belonging to the genus Enterovirus in the family Picornaviridae. In 2008 the Poliovirus species was eliminated from the genus Enterovirus and the three serotypes were assigned to the species Human enterovirus C, in the genus Enterovirus in the family Picornaviridae. The type species of the genus Enterovirus was changed from Poliovirus to Human enterovirus C.
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 (outside of laboratories) only on the cells of humans, higher primates, and Old World monkey
s. Poliovirus is however strictly a human pathogen, and does not naturally infect any other species (although chimpanzee
s and Old World monkeys can be experimentally infected).
The CD155 gene appears to have been subject to positive selection. The protein has several domains of which domain D1 contains the polio virus binding site. Within this domain 37 amino acids are responsible for binding the virus.
Poliovirus is an enterovirus
. Infection occurs via the fecal-oral route
, meaning that one ingests the virus and viral replication occurs in the alimentary tract. Virus is shed in the feces of infected individuals. In 95% of cases only a primary, transient presence of viremia
(virus in the bloodstream) occurs, and the poliovirus infection is asymptomatic
. In about 5% of cases, the virus spreads and replicates in other sites such as brown fat, reticuloendothelial tissue, and muscle
. The sustained viral replication causes secondary viremia and leads to the development of minor symptoms such as fever, headache and sore throat. Paralytic poliomyelitis occurs in less than 1% of poliovirus infections. Paralytic disease occurs when the virus enters the central nervous system
(CNS) and replicates in motor neuron
s within the spinal cord
, brain stem
, or motor cortex
, resulting in the selective destruction of motor neurons leading to temporary or permanent paralysis
. In rare cases, paralytic poliomyelitis leads to respiratory arrest
and death. In cases of paralytic disease, muscle pain and spasms are frequently observed prior to onset of weakness and paralysis. Paralysis typically persists anywhere from days to weeks prior to recovery.
In many respects the neurological phase of infection is thought to be an accidental diversion of the normal gastrointestinal infection. The mechanisms by which poliovirus enters the CNS are poorly understood. Three non-mutually exclusive hypotheses have been suggested to explain its entry. All theories require primary viremia. The first hypothesis predicts that virions pass directly from the blood
into the central nervous system by crossing the blood brain barrier independent of CD155. A second hypothesis suggests that the virions are transported from peripheral tissues that have been bathed in the viremic blood, for example muscle tissue, to the spinal cord through nerve pathways via retrograde axonal transport. A third hypothesis is that the virus is imported into the CNS via infected monocyte
s or macrophage
s.
Poliomyelitis is a disease of the central nervous system. However, CD155 is believed to be present on the surface of most or all human cells. Therefore receptor expression does not explain why poliovirus preferentially infects certain tissues. This suggests that tissue tropism
is determined after cellular 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 support poliovirus replication. In mice expressing CD155 (through genetic engineering) but lacking the type I interferon receptor, poliovirus not only replicates in an expanded repertoire of tissue types, but these mice are also able to be infected orally with the virus.
. 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
. Second, because it can replicate very quickly, the virus overwhelms the host organs before an immune response can be mounted.
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 tonsil
s 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. Infection with one serotype of poliovirus does not provide immunity against the other serotypes, however second attacks within the same individual are extremely rare.
to express a human receptor to poliovirus (hPVR).
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
. 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.
Three distinct types of TgPVR mice have been well studied:
Recently a fourth 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.
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.
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. 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. 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. Enzyme
s were used to convert the DNA back into RNA, its natural state. Other enzymes were then used to translate the RNA into a polypeptide, producing functional viral particle. 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.
Poliomyelitis
Poliomyelitis, often called polio or infantile paralysis, is an acute viral infectious disease spread from person to person, primarily via the fecal-oral route...
, is a human enterovirus
Enterovirus
Enteroviruses are a genus of ssRNA viruses associated with several human and mammalian diseases. Serologic studies have distinguished 66 human enterovirus serotypes on the basis of antibody neutralization tests. Additional antigenic variants have been defined within several of the serotypes on the...
and member of the family of Picornaviridae.
Poliovirus is composed of an RNA
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....
genome
Genome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....
and a protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
capsid. The genome is a single-stranded positive-sense
Sense (molecular biology)
In molecular biology and genetics, sense is a concept used to compare the polarity of nucleic acid molecules, such as DNA or RNA, to other nucleic acid molecules...
RNA genome that is about 7500 nucleotide
Nucleotide
Nucleotides are molecules that, when joined together, make up the structural units of RNA and DNA. In addition, nucleotides participate in cellular signaling , and are incorporated into important cofactors of enzymatic reactions...
s long. The viral particle is about 30 nanometre
Nanometre
A nanometre is a unit of length in the metric system, equal to one billionth of a metre. The name combines the SI prefix nano- with the parent unit name metre .The nanometre is often used to express dimensions on the atomic scale: the diameter...
s in diameter with icosahedral symmetry
Icosahedral symmetry
A regular icosahedron has 60 rotational symmetries, and a symmetry order of 120 including transformations that combine a reflection and a rotation...
. Because of its short genome and its simple composition—only RNA and a non-enveloped
Viral envelope
Many viruses have viral envelopes covering their protein capsids. The envelopes typically are derived from portions of the host cell membranes , but include some viral glycoproteins. Functionally, viral envelopes are used to help viruses enter host cells...
icosahedral protein coat that encapsulates
Capsid
A capsid is the protein shell of a virus. It consists of several oligomeric structural subunits made of protein called protomers. The observable 3-dimensional morphological subunits, which may or may not correspond to individual proteins, are called capsomeres. The capsid encloses the genetic...
it—poliovirus is widely regarded as the simplest significant virus.
Poliovirus was first isolated in 1909 by Karl Landsteiner
Karl Landsteiner
Karl Landsteiner , was an Austrian-born American biologist and physician of Jewish origin. He is noted for having first distinguished the main blood groups in 1900, having developed the modern system of classification of blood groups from his identification of the presence of agglutinins in the...
and Erwin Popper
Erwin Popper
Erwin Popper , was an Austrian physician, who, in 1908, along with Karl Landsteiner discovered the infectious character of Poliomyelitis....
. In 1981, the poliovirus genome was published by two different teams of researchers— by Vincent Racaniello
Vincent Racaniello
Vincent R. Racaniello is a Higgins Professor in the Department of Microbiology and Immunology at Columbia University’s College of Physicians and Surgeons...
and David Baltimore
David Baltimore
David Baltimore is an American biologist, university administrator, and Nobel laureate in Physiology or Medicine. He served as president of the California Institute of Technology from 1997 to 2006, and is currently the Robert A. Millikan Professor of Biology at Caltech...
at MIT
Massachusetts Institute of Technology
The Massachusetts Institute of Technology is a private research university located in Cambridge, Massachusetts. MIT has five schools and one college, containing a total of 32 academic departments, with a strong emphasis on scientific and technological education and research.Founded in 1861 in...
and by Naomi Kitamura and others at the State University of New York, Stony Brook. Poliovirus is one of the most well-characterized viruses, and has become a useful model system for understanding the biology of RNA viruses.
Life cycle
CD155
CD155 also known as the poliovirus receptor is a protein that in humans is encoded by the PVR gene.- Function :CD155 is a Type I transmembrane glycoprotein in the immunoglobulin superfamily...
, (also known as the poliovirus receptor (PVR)) on the cell surface. Interaction of poliovirus and CD155 facilitates an irreversible conformational change of the viral particle necessary for viral entry. The precise mechanism poliovirus uses to enter the host
Host (biology)
In biology, a host is an organism that harbors a parasite, or a mutual or commensal symbiont, typically providing nourishment and shelter. In botany, a host plant is one that supplies food resources and substrate for certain insects or other fauna...
cell has not been firmly established. Attached to the host cell membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
, entry of the viral nucleic acid was thought to occur one of two ways: via the formation of a pore
Nuclear pore
Nuclear pores are large protein complexes that cross the nuclear envelope, which is the double membrane surrounding the eukaryotic cell nucleus. There are about on average 2000 nuclear pore complexes in the nuclear envelope of a vertebrate cell, but it varies depending on cell type and the stage in...
in the plasma membrane through which the RNA is then “injected” into the host cell cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
, or that the virus is taken up by receptor-mediated endocytosis
Receptor-mediated endocytosis
Receptor-mediated endocytosis , also called clathrin-dependent endocytosis, is a process by which cells internalize molecules by the inward budding of plasma membrane vesicles containing proteins with receptor sites specific to the molecules being internalized.-Process:After the binding of a...
. 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. However, any mechanism by which poliovirus enters the cell is very inefficient; as an infection is initiated only about 1% of the time.
Poliovirus is a positive stranded RNA virus
RNA virus
An RNA virus is a virus that has RNA as its genetic material. This nucleic acid is usually single-stranded RNA but may be double-stranded RNA...
. Thus the genome enclosed within the viral particle can be used as messenger RNA
Messenger RNA
Messenger RNA is a molecule of RNA encoding a chemical "blueprint" for a protein product. mRNA is transcribed from a DNA template, and carries coding information to the sites of protein synthesis: the ribosomes. Here, the nucleic acid polymer is translated into a polymer of amino acids: a protein...
and immediately translated by the host cell. On entry the virus hijacks the cell's translation machinery; causing inhibition of cellular protein synthesis in favor of virus–specific protein production. Unlike the host cell's mRNAs the 5' end
Directionality (molecular biology)
Directionality, in molecular biology and biochemistry, is the end-to-end chemical orientation of a single strand of nucleic acid. The chemical convention of naming carbon atoms in the nucleotide sugar-ring numerically gives rise to a 5′-end and a 3′-end...
of poliovirus RNA is extremely long—over 700 nucleotides—and is highly structured. This region of the viral genome is called internal ribosome entry site
Internal ribosome entry site
An internal ribosome entry site, abbreviated IRES, is a nucleotide sequence that allows for translation initiation in the middle of a messenger RNA sequence as part of the greater process of protein synthesis...
(IRES) and it directs translation of the viral RNA. Genetic mutations in this region prevent viral protein production.
Poliovirus mRNA is translated as one long polypeptide. This polypeptide is then auto-cleaved by internal proteases into approximately 10 individual viral proteins, including:
- 3Dpol, an RNA dependent RNA polymerase whose function is to copy and multiply the viral RNA genome.
- 2Apro and 3Cpro/3CDpro, proteaseProteaseA protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein....
s which cleave the viral polypeptide. - VPgVPgVPg is a protein attached to the 5' end of RNA during RNA synthesis in a wide variety of viruses including Picornaviridae such as Foot-and-mouth disease and poliovirus . VPg stands for "viral protein genome-linked".-Attachment during RNA synthesis:...
(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 not fully understood. Fully assembled poliovirus leaves the confines of its host cell 4 to 6 hours following initiation of infection in cultured mammalian cells. The mechanism of viral release from the cell is unclear, but each dying cell can release up to 10,000 polio virions.
Origin and serotypes
Poliovirus is structurally similar to other human enteroviruses (coxsackievirusCoxsackievirus
Coxsackievirus is a virus that belongs to a family of non enveloped linear positive-sense ssRNA viruses, Picornaviridae and the genus Enterovirus, which also includes poliovirus and echovirus. Enteroviruses are among the most common and important human pathogens and ordinarily its members are...
es and echovirus
Echovirus
An ECHO virus, is a type of RNA virus that belongs to the genus Enterovirus of the Picornaviridae family...
es), as well as to human rhinovirus
Rhinovirus
Human rhinoviruses are the most common viral infective agents in humans and are the predominant cause of the common cold. Rhinovirus infection proliferates in temperatures between 33–35 °C , and this may be why it occurs primarily in the nose...
es, which also use immunoglobulin-like molecules to recognize and enter host cells. Phylogenetic analysis of the RNA and protein sequences of poliovirus (PV) suggests that PV may have evolved from a C-cluster coxsackie A virus
Coxsackie A virus
Coxsackie A virus is a cytolytic coxsackie virus of the Picornaviridae family, an enterovirus .-Diseases:...
ancestor
Common descent
In evolutionary biology, a group of organisms share common descent if they have a common ancestor. There is strong quantitative support for the theory that all living organisms on Earth are descended from a common ancestor....
, that arose through a mutation within the capsid. The distinct speciation
Speciation
Speciation is the evolutionary process by which new biological species arise. The biologist Orator F. Cook seems to have been the first to coin the term 'speciation' for the splitting of lineages or 'cladogenesis,' as opposed to 'anagenesis' or 'phyletic evolution' occurring within lineages...
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
CD155
CD155 also known as the poliovirus receptor is a protein that in humans is encoded by the PVR gene.- Function :CD155 is a Type I transmembrane glycoprotein in the immunoglobulin superfamily...
; leading to a change in pathogenicity, and allowing the virus to infect nervous tissue.
The mutation rate in the virus is relatively high even for an RNA virus with a synonymous substitution rate of 1.0 x 10-2 substitutions/site/year and
non synomymous subtitution rate of 3.0 x 10-4 substitutions/site/year. Base distribution within the genome is non random with adenosine being less common than expected at the 5' end and higher at the 3' end. Codon use is non random with codons ending in adenosine being favourec and those ending in cytosine
Cytosine
Cytosine is one of the four main bases found in DNA and RNA, along with adenine, guanine, and thymine . It is a pyrimidine derivative, with a heterocyclic aromatic ring and two substituents attached . The nucleoside of cytosine is cytidine...
or guanine
Guanine
Guanine is one of the four main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine . In DNA, guanine is paired with cytosine. With the formula C5H5N5O, guanine is a derivative of purine, consisting of a fused pyrimidine-imidazole ring system with...
being avoided. Codon use differs between the three genotypes and appears to be driven by mutation rather than selection.
There are three serotype
Serotype
Serotype or serovar refers to distinct variations within a subspecies of bacteria or viruses. These microorganisms, viruses, or cells are classified together based on their cell surface antigens...
s of poliovirus, PV1, PV2 , and PV3; each with a slightly different capsid
Capsid
A capsid is the protein shell of a virus. It consists of several oligomeric structural subunits made of protein called protomers. The observable 3-dimensional morphological subunits, which may or may not correspond to individual proteins, are called capsomeres. The capsid encloses the genetic...
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
Infectious disease
Infectious diseases, also known as communicable diseases, contagious diseases or transmissible diseases comprise clinically evident illness resulting from the infection, presence and growth of pathogenic biological agents in an individual host organism...
. Wild polioviruses can be found in approximately 10 countries. PV1 is highly localized to regions in India, Pakistan, Afghanistan, and Egypt, but following outbreaks of poliomeyletis in 2003–2004 it remains widespread in West and Central Africa. Wild poliovirus type 2 has probably been eradicated; it was last detected in October 1999 in Uttar Pradesh
Uttar Pradesh
Uttar Pradesh abbreviation U.P. , is a state located in the northern part of India. With a population of over 200 million people, it is India's most populous state, as well as the world's most populous sub-national entity...
, India. Wild PV3 is found in parts of only five countries (Nigeria, Niger, Pakistan, India, and Sudan).
Specific strains of each serotype are used to prepare vaccines against polio
Polio vaccine
Two polio vaccines are used throughout the world to combat poliomyelitis . The first was developed by Jonas Salk and first tested in 1952. Announced to the world by Salk on April 12, 1955, it consists of an injected dose of inactivated poliovirus. An oral vaccine was developed by Albert Sabin...
. Inactive polio vaccine (IPV) is prepared by formalin inactivation of three wild, virulent reference strains, Mahoney or Brunenders (PV1), MEF-1/Lansing (PV2), and Saukett/Leon (PV3). Oral polio vaccine (OPV) contains live attenuated (weakened) strains of the three serotypes of poliovirus. Passaging the virus strains in monkey kidney epithelial cells introduces mutations in the viral IRES, and hinders (or attenuates) the ability of the virus to infect nervous tissue.
Polioviruses were formerly classified as a distinct species belonging to the genus Enterovirus in the family Picornaviridae. In 2008 the Poliovirus species was eliminated from the genus Enterovirus and the three serotypes were assigned to the species Human enterovirus C, in the genus Enterovirus in the family Picornaviridae. The type species of the genus Enterovirus was changed from Poliovirus to Human enterovirus C.
Pathogenesis
Old World monkey
The Old World monkeys or Cercopithecidae are a group of primates, falling in the superfamily Cercopithecoidea in the clade Catarrhini. The Old World monkeys are native to Africa and Asia today, inhabiting a range of environments from tropical rain forest to savanna, shrubland and mountainous...
s. Poliovirus is however strictly a human pathogen, and does not naturally infect any other species (although chimpanzee
Chimpanzee
Chimpanzee, sometimes colloquially chimp, is the common name for the two extant species of ape in the genus Pan. The Congo River forms the boundary between the native habitat of the two species:...
s and Old World monkeys can be experimentally infected).
The CD155 gene appears to have been subject to positive selection. The protein has several domains of which domain D1 contains the polio virus binding site. Within this domain 37 amino acids are responsible for binding the virus.
Poliovirus is an enterovirus
Enterovirus
Enteroviruses are a genus of ssRNA viruses associated with several human and mammalian diseases. Serologic studies have distinguished 66 human enterovirus serotypes on the basis of antibody neutralization tests. Additional antigenic variants have been defined within several of the serotypes on the...
. Infection occurs via the fecal-oral route
Fecal-oral route
The fecal-oral route, or alternatively, the oral-fecal route or orofecal route is a route of transmission of diseases, in which they are passed when pathogens in fecal particles from one host are introduced into the oral cavity of another potential host.There are usually intermediate steps,...
, meaning that one ingests the virus and viral replication occurs in the alimentary tract. Virus is shed in the feces of infected individuals. In 95% of cases only a primary, transient presence of viremia
Viremia
Viremia is a medical condition where viruses enter the bloodstream and hence have access to the rest of the body. It is similar to bacteremia, a condition where bacteria enter the bloodstream.- Primary versus Secondary :...
(virus in the bloodstream) occurs, and the poliovirus infection is asymptomatic
Asymptomatic
In medicine, a disease is considered asymptomatic if a patient is a carrier for a disease or infection but experiences no symptoms. A condition might be asymptomatic if it fails to show the noticeable symptoms with which it is usually associated. Asymptomatic infections are also called subclinical...
. In about 5% of cases, the virus spreads and replicates in other sites such as brown fat, reticuloendothelial tissue, and muscle
Muscle
Muscle is a contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...
. The sustained viral replication causes secondary viremia and leads to the development of minor symptoms such as fever, headache and sore throat. Paralytic poliomyelitis occurs in less than 1% of poliovirus infections. Paralytic disease occurs when the virus enters the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
(CNS) and replicates in motor neuron
Motor neuron
In vertebrates, the term motor neuron classically applies to neurons located in the central nervous system that project their axons outside the CNS and directly or indirectly control muscles...
s within the spinal cord
Spinal cord
The spinal cord is a long, thin, tubular bundle of nervous tissue and support cells that extends from the brain . The brain and spinal cord together make up the central nervous system...
, brain stem
Brain stem
In vertebrate anatomy the brainstem is the posterior part of the brain, adjoining and structurally continuous with the spinal cord. The brain stem provides the main motor and sensory innervation to the face and neck via the cranial nerves...
, or motor cortex
Motor cortex
Motor cortex is a term that describes regions of the cerebral cortex involved in the planning, control, and execution of voluntary motor functions.-Anatomy of the motor cortex :The motor cortex can be divided into four main parts:...
, resulting in the selective destruction of motor neurons leading to temporary or permanent paralysis
Paralysis
Paralysis is loss of muscle function for one or more muscles. Paralysis can be accompanied by a loss of feeling in the affected area if there is sensory damage as well as motor. A study conducted by the Christopher & Dana Reeve Foundation, suggests that about 1 in 50 people have been diagnosed...
. In rare cases, paralytic poliomyelitis leads to respiratory arrest
Respiratory arrest
Respiratory arrest is the cessation of breathing. It is a medical emergency and it usually is related to or coincides with a cardiac arrest. Causes include opiate overdose, head injury, anaesthesia, tetanus, or drowning...
and death. In cases of paralytic disease, muscle pain and spasms are frequently observed prior to onset of weakness and paralysis. Paralysis typically persists anywhere from days to weeks prior to recovery.
In many respects the neurological phase of infection is thought to be an accidental diversion of the normal gastrointestinal infection. The mechanisms by which poliovirus enters the CNS are poorly understood. Three non-mutually exclusive hypotheses have been suggested to explain its entry. All theories require primary viremia. The first hypothesis predicts that virions pass directly from the blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
into the central nervous system by crossing the blood brain barrier independent of CD155. A second hypothesis suggests that the virions are transported from peripheral tissues that have been bathed in the viremic blood, for example muscle tissue, to the spinal cord through nerve pathways via retrograde axonal transport. A third hypothesis is that the virus is imported into the CNS via infected monocyte
Monocyte
Monocytes are a type of white blood cell and are part of the innate immune system of vertebrates including all mammals , birds, reptiles, and fish. Monocytes play multiple roles in immune function...
s or macrophage
Macrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
s.
Poliomyelitis is a disease of the central nervous system. However, CD155 is believed to be present on the surface of most or all human cells. Therefore receptor expression does not explain why poliovirus preferentially infects certain tissues. This suggests that tissue tropism
Tropism
A tropism is a biological phenomenon, indicating growth or turning movement of a biological organism, usually a plant, in response to an environmental stimulus. In tropisms, this response is dependent on the direction of the stimulus...
is determined after cellular infection. Recent work has suggested that the type I interferon
Interferon type I
Human type I interferons comprise a vast and growing group of IFN proteins.All type I IFNs bind to a specific cell surface receptor complex known as the IFN-α receptor that consists of IFNAR1 and IFNAR2 chains....
response (specifically that of interferon alpha and beta) is an important factor that defines which types of cells support poliovirus replication. In mice expressing CD155 (through genetic engineering) but lacking the type I interferon receptor, poliovirus not only replicates in an expanded repertoire of tissue types, but these mice are also able to be infected orally with the virus.
Immune system avoidance
Poliovirus uses two key mechanisms to evade the immune systemImmune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
. First, it is capable of surviving the highly acidic
PH
In chemistry, pH is a measure of the acidity or basicity of an aqueous solution. Pure water is said to be neutral, with a pH close to 7.0 at . Solutions with a pH less than 7 are said to be acidic and solutions with a pH greater than 7 are basic or alkaline...
conditions of the gastrointestinal tract
Gastrointestinal tract
The human gastrointestinal tract refers to the stomach and intestine, and sometimes to all the structures from the mouth to the anus. ....
, allowing the virus to infect the host and spread throughout the body via the lymphatic system
Lymphatic system
The lymphoid system is the part of the immune system comprising a network of conduits called lymphatic vessels that carry a clear fluid called lymph unidirectionally toward the heart. Lymphoid tissue is found in many organs, particularly the lymph nodes, and in the lymphoid follicles associated...
. Second, because it can replicate very quickly, the virus overwhelms the host organs before an immune response can be mounted.
Individuals who are exposed to poliovirus, either through infection or by immunization
Immunization
Immunization, or immunisation, is the process by which an individual's immune system becomes fortified against an agent ....
with polio vaccine
Polio vaccine
Two polio vaccines are used throughout the world to combat poliomyelitis . The first was developed by Jonas Salk and first tested in 1952. Announced to the world by Salk on April 12, 1955, it consists of an injected dose of inactivated poliovirus. An oral vaccine was developed by Albert Sabin...
, develop immunity
Immunity (medical)
Immunity is a biological term that describes a state of having sufficient biological defenses to avoid infection, disease, or other unwanted biological invasion. Immunity involves both specific and non-specific components. The non-specific components act either as barriers or as eliminators of wide...
. In immune individuals, antibodies against poliovirus are present in the tonsil
Tonsil
Palatine tonsils, occasionally called the faucial tonsils, are the tonsils that can be seen on the left and right sides at the back of the throat....
s and gastrointestinal tract (specifically IgA
IGA
Iga or IGA may stand for:-Given name:* a female given name of Polish origin. The name originates from the female given name Jadwiga and stands for gia,or gina in the USA....
antibodies) and are able to block poliovirus replication; IgG and IgM
IGM
IGM as an acronym or abbreviation can refer to:* Immunoglobulin M , the primary antibody against A and B antigens on red blood cells* International Grandmaster, a chess ranking* intergalactic medium* Intragroup medium - see: Intracluster medium...
antibodies against poliovirus can prevent the spread of the virus to motor neurons of the central nervous system. 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 engineeredGenetic engineering
Genetic engineering, also called genetic modification, is the direct human manipulation of an organism's genome using modern DNA technology. It involves the introduction of foreign DNA or synthetic genes into the organism of interest...
to express a human receptor to poliovirus (hPVR).
Unlike normal mice, transgenic poliovirus receptor (TgPVR) mice are susceptible to poliovirus injected intravenously or intramuscularly, and when injected directly into the spinal cord
Spinal cord
The spinal cord is a long, thin, tubular bundle of nervous tissue and support cells that extends from the brain . The brain and spinal cord together make up the central nervous system...
or the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
. 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
Histopathology
Histopathology refers to the microscopic examination of tissue in order to study the manifestations of disease...
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.
Three distinct types of TgPVR mice have been well studied:
- In TgPVR1 mice the transgene encoding the human PVR was incorporated into mouse chromosomeChromosomeA chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
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.
- 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 fourth TgPVR mouse model was developed. These "cPVR" mice carry hPVR cDNA, driven by a β-actin
Actin
Actin is a globular, roughly 42-kDa moonlighting protein found in all eukaryotic cells where it may be present at concentrations of over 100 μM. It is also one of the most highly-conserved proteins, differing by no more than 20% in species as diverse as algae and humans...
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.
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
World Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...
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.
Cloning and synthesis
Molecular cloning
Molecular cloning refers to a set of experimental methods in molecular biology that are used to assemble recombinant DNA molecules and to direct their replication within host organisms...
of an animal RNA virus, poliovirus. DNA encoding the RNA genome of poliovirus was introduced into cultured mammalian cells and infectious poliovirus was produced. 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. 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
Gene synthesis
Artificial gene synthesis is the process of synthesizing a gene in vitro without the need for initial template DNA samples. The main method is currently by oligonucleotide synthesis from digital genetic sequences and subsequent annealing of the resultant fragments...
company. This whole painstaking process took two years. Nineteen markers
Marker gene
A marker gene is a gene used in molecular biology to determine if a nucleic acid sequence has been successfully inserted into an organism's DNA. There are two types of marker genes: a selectable marker and a marker for screening.-Selectable marker:...
were incorporated into the synthesized DNA, so that it could be distinguished from natural poliovirus. Enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s were used to convert the DNA back into RNA, its natural state. Other enzymes were then used to translate the RNA into a polypeptide, producing functional viral particle. 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.