Human bocavirus
Encyclopedia
Human bocavirus is a parvovirus
that has been suggested to cause human disease. It is a probable cause of lower respiratory tract infection
s and it has been linked to gastroenteritis
, although the role of this emerging infectious disease in human disease has not been firmly established.
in Stockholm, Sweden, first cloned this new member of the family of Parvoviridae
in 2005 from pooled nasopharyngeal aspirates (NPA, collection of aspirated fluid from the back of the nasal cavity). They used a novel technique called molecular virus screening, based on random cloning
and bioinformatical
analysis. This technique has led to the discovery of new viruses such as polyomavirus
KI (Karolinska Institute) and WU (Washington University), which are closely related to each other and have been isolated from respiratory secretions.
Several groups of scientists have since then found that HBoV is the fourth most common virus in respiratory samples, behind respiratory syncytial virus, adenoviruses (155, 28%) and rhinovirus
es.
The name bocavirus is derived from bovine and canine, referring to the two known hosts for other members of this genus; the bovine parvovirus
which infects cattle, and the minute virus of canines which infects dogs. Parvoviruses (Latin: small viruses) have a 5 kilobase long single-stranded DNA
, and they use some of their host's replication
proteins to copy their DNA.
s are small (diameter 18-26 nanometers), icosahedral and non enveloped. The capsid has a T = 1 symmetry and consists of 60 copies of coat protein
. The coat proteins have a conserved, eight stranded beta barrel motif that forms the core of the capsid. There is also a conserved alpha helix.
The HBoV capsid shares three characteristic features also found in the other vertebrate parvoviruses: (1) a dimple like depression at each icosahedral 2-fold axis; (2) a large trimeric protrusion surrounds each 3-fold axis or is located at the 3-fold axis; (3) a channel at each 5-fold axis whose outermost opening is formed by a small pentameric structure encircled by a wide canyon like region. While this dimple is also found among the invertebrate parvoviruses they lack the 3-fold protrusions and canyon around the 5-fold channel. The external diameter of the capsid ranges from ∼21.5 nanometers (nm) at the lowest points of the dimple and canyon to ∼28 nm at the top of the protrusion.
The genome
is a linear, single-stranded DNA 5.2-5.3 kilobases in length with terminal hairpin structures at both ends.
The genome encodes 3 open reading frames (ORF1, 2 and 3). The two left most ORFs encode 2 non structural proteins (NS1 and NP1). The right hand ORF (ORF3) encodes the capsid proteins (VP1 and VP2). The NP1 gene is in an alternate reading frame to VP1 and overlaps the start of VP1 by 13 nucleotides. Similarly, VP2 is collinear to VP1 and results from initiation of translation at a downstream ATG and co-terminates.
NP1 is a highly phosphorylated non structural protein whose function is not yet understood.
There is a single promoter
located within the 3' hairpin. This is responsible for, by alternative splicing and alternative polyadenylation, for the generation of several (at least 6) mRNA
s. The poly A tail is ~150 nucleotides in length.
After nuclear import the single stranded genome is converted to double stranded DNA and production of the viral NS1 protein commences.
The genome is replicated through a unique rolling hairpin mechanism that is dependent on the NS1 protein.
A sequence conserved among the Parvoviridae TAAAAAT is found close to the 3' terminus.
Other parvoviruses replicate only when the host cell is in S phase: viral replication results in the death of the host cell. This pattern has not yet been experimentally confirmed for the bocaviruses but seems likely to be the case. Expression of the viral proteins alone does not cause host cell death. unlike other parvoviruses where this has been examined.
The receptor for bovine parvovirus 1 is sialic acid
.
s all of which travel along DNA in a 3′-to-5′ direction. Four conserved sequence motifs in are found in SF3 helicases (A, B, B′, and C). These motifs form the nucleoside triphosphate binding pocket, the metal ion coordination site, the DNA-binding site and the sensory element. These motifs are in a stretch of approximately 100 amino acid residues in the middle of NS1. These helicases surround DNA as a ring of six or eight subunits with the ATP binding pocket lying between adjacent subunits. The first subunit provides the A and B motifs, and the arginine
residue of the second subunit functions as a trans-acting arginine finger sensor for ATP binding and hydrolysis status. The arginine finger lies after the C motif but in three dimensions it is often embedded in a cluster of positively charged amino acids. In a ring configuration this domain interacts with the ATP binding pocket of the neighboring subunit.
NS1 binds to both the left and right hand origins of replication on the right with the host's own high mobility group
proteins and on the left with glucocorticoid
modulatory element-binding proteins. Origin recognition leads to strand- and site-specific nicking of viral DNA, processes that require ATP for tight binding and subsequent nicking. The NS1 protein remains covalently linked to the 5′ end of nicked DNA with the 3′-hydroxyl group being used for synthesis of the nascent strand. Replication of the genome is thought to be mediated by DNA polymerase
δ. This polymerase is usually involved in repair of DNA after the excision of nucleotides. This process involves proliferating cell nuclear antigen, the single strand-binding protein replication protein A
and NS1. In this process NS1 acts as an ATP powered helicase to resolve terminal hairpin structures of the viral genome.
In addition to these functions NS1 enhances transcription from a viral capsid promoter, may assist in packing DNA into newly formed capsids and is responsible for the cytopathic effect of parvoviruses.
There are four genotypes from humans of this virus are known - type 1 to 4. Types 1 and 2 appear to have diverged recently (circa 1985) Recombination may occur between strains. The estimated mean evolutionary rate is 8.6 x 10(-4) substitutions/site/year. The 1st + 2nd codon positions evolve 15 times more slowly than those of the 3rd codon position.
Phylogenetic analysis of this genus groups the swine bocavirus with canine minute virus.
Bocaviruses have been isolated from pigs
Human bocavirus 3 appears to be a recombinant of human bocavirus 1 and human bocavirus 2 and 4.
Incomplete sequences of bocaviruses have been obtained from wild chimpanzees. These sequences phlyogenetically lie within the known human bocavirus isolates but also show evidence of recombination.
Newborns are probably protected by passive immunisation.
The age group most frequently affected appear to be children between the ages of six months to two years, although cases in children older than five and even in a 28-year-old have been reported.
HBoV can be detected not only in respiratory samples but also in blood, urine and stools. The latter two may merely reflect viral shedding, although diarrhoea has been described in animal bocaviral infections, and some patients with HBoV seem to have diarrhoea independent of respiratory symptoms.
A study in Jordan found that 9% of 220 children hospitalised with lower respiratory tract infection were infected with bocavirus. Of those infeced the median age was 4 months. Coughing (100%), wheezing (82.7%) and fever (68.2%) were the most common clinical findings with bronchopneumonia (35%) and bronchiolitis (30%) being the most common ultimate diagnoses.
HBoV1 has been generally associated with respiratory symptoms while other HBoV tend to be associated with diarrhea and acute flaccid paralysis.
Parvovirus
Parvovirus, often truncated to "parvo", is both the common name in English casually applied to all the viruses in the Parvoviridae taxonomic family, and also the taxonomic name of the Parvovirus genus within the Parvoviridae family...
that has been suggested to cause human disease. It is a probable cause of lower respiratory tract infection
Lower respiratory tract infection
Lower respiratory tract infection while often used as a synonym for pneumonia, can also be applied to other types of infection including lung abscess and acute bronchitis...
s and it has been linked to gastroenteritis
Gastroenteritis
Gastroenteritis is marked by severe inflammation of the gastrointestinal tract involving both the stomach and small intestine resulting in acute diarrhea and vomiting. It can be transferred by contact with contaminated food and water...
, although the role of this emerging infectious disease in human disease has not been firmly established.
History
Allander and colleagues at the Karolinska InstitutetKarolinska Institutet
Karolinska institutet is a medical university in Solna within the Stockholm urban area, Sweden, and one of Europe's largest medical universities...
in Stockholm, Sweden, first cloned this new member of the family of Parvoviridae
Parvoviridae
The Parvoviridae family includes the smallest known viruses, and some of the most environmentally resistant. They were discovered during the 1960s and affect vertebrates and insects...
in 2005 from pooled nasopharyngeal aspirates (NPA, collection of aspirated fluid from the back of the nasal cavity). They used a novel technique called molecular virus screening, based on random cloning
Cloning
Cloning in biology is the process of producing similar populations of genetically identical individuals that occurs in nature when organisms such as bacteria, insects or plants reproduce asexually. Cloning in biotechnology refers to processes used to create copies of DNA fragments , cells , or...
and bioinformatical
Bioinformatics
Bioinformatics is the application of computer science and information technology to the field of biology and medicine. Bioinformatics deals with algorithms, databases and information systems, web technologies, artificial intelligence and soft computing, information and computation theory, software...
analysis. This technique has led to the discovery of new viruses such as polyomavirus
Polyomavirus
Polyomavirus is the sole genus of viruses within the family Polyomaviridæ. Murine polyomavirus was the first polyomavirus discovered by Ludwik Gross in 1953. Subsequently, many polyomaviruses have been found to infect birds and mammals...
KI (Karolinska Institute) and WU (Washington University), which are closely related to each other and have been isolated from respiratory secretions.
Several groups of scientists have since then found that HBoV is the fourth most common virus in respiratory samples, behind respiratory syncytial virus, adenoviruses (155, 28%) and 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.
The name bocavirus is derived from bovine and canine, referring to the two known hosts for other members of this genus; the bovine parvovirus
Bovine parvovirus
Bovine parvovirus , also known as Haemadsorbing Enteric Virus, is a member of the parvivirus group, with three significant sub-species: BPV1, 2 and 3. BPV most commonly causes diarrhoea in neonatal calves and respiratory and reproductive disease in adult cattle. The distribution of the virus is...
which infects cattle, and the minute virus of canines which infects dogs. Parvoviruses (Latin: small viruses) have a 5 kilobase long single-stranded DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
, and they use some of their host's replication
Cell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
proteins to copy their DNA.
Virology
The vironViron
Viron may refer to:*Viron, a Finnish word for "Estonia's" or "of Estonia"*Viron, a Greek form of Byron and an alternative form of the city of Vyronas in suburban Athens, Greece...
s are small (diameter 18-26 nanometers), icosahedral and non enveloped. The capsid has a T = 1 symmetry and consists of 60 copies of coat 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...
. The coat proteins have a conserved, eight stranded beta barrel motif that forms the core of the capsid. There is also a conserved alpha helix.
The HBoV capsid shares three characteristic features also found in the other vertebrate parvoviruses: (1) a dimple like depression at each icosahedral 2-fold axis; (2) a large trimeric protrusion surrounds each 3-fold axis or is located at the 3-fold axis; (3) a channel at each 5-fold axis whose outermost opening is formed by a small pentameric structure encircled by a wide canyon like region. While this dimple is also found among the invertebrate parvoviruses they lack the 3-fold protrusions and canyon around the 5-fold channel. The external diameter of the capsid ranges from ∼21.5 nanometers (nm) at the lowest points of the dimple and canyon to ∼28 nm at the top of the protrusion.
The 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....
is a linear, single-stranded DNA 5.2-5.3 kilobases in length with terminal hairpin structures at both ends.
The genome encodes 3 open reading frames (ORF1, 2 and 3). The two left most ORFs encode 2 non structural proteins (NS1 and NP1). The right hand ORF (ORF3) encodes the capsid proteins (VP1 and VP2). The NP1 gene is in an alternate reading frame to VP1 and overlaps the start of VP1 by 13 nucleotides. Similarly, VP2 is collinear to VP1 and results from initiation of translation at a downstream ATG and co-terminates.
NP1 is a highly phosphorylated non structural protein whose function is not yet understood.
There is a single promoter
Promoter
In genetics, a promoter is a region of DNA that facilitates the transcription of a particular gene. Promoters are located near the genes they regulate, on the same strand and typically upstream .-Overview:...
located within the 3' hairpin. This is responsible for, by alternative splicing and alternative polyadenylation, for the generation of several (at least 6) mRNA
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...
s. The poly A tail is ~150 nucleotides in length.
After nuclear import the single stranded genome is converted to double stranded DNA and production of the viral NS1 protein commences.
The genome is replicated through a unique rolling hairpin mechanism that is dependent on the NS1 protein.
A sequence conserved among the Parvoviridae TAAAAAT is found close to the 3' terminus.
Other parvoviruses replicate only when the host cell is in S phase: viral replication results in the death of the host cell. This pattern has not yet been experimentally confirmed for the bocaviruses but seems likely to be the case. Expression of the viral proteins alone does not cause host cell death. unlike other parvoviruses where this has been examined.
The receptor for bovine parvovirus 1 is sialic acid
Sialic acid
Sialic acid is a generic term for the N- or O-substituted derivatives of neuraminic acid, a monosaccharide with a nine-carbon backbone. It is also the name for the most common member of this group, N-acetylneuraminic acid...
.
Molecular biology
NS1 belongs to the superfamily III (SF3) helicaseHelicase
Helicases are a class of enzymes vital to all living organisms. They are motor proteins that move directionally along a nucleic acid phosphodiester backbone, separating two annealed nucleic acid strands using energy derived from ATP hydrolysis.-Function:Many cellular processes Helicases are a...
s all of which travel along DNA in a 3′-to-5′ direction. Four conserved sequence motifs in are found in SF3 helicases (A, B, B′, and C). These motifs form the nucleoside triphosphate binding pocket, the metal ion coordination site, the DNA-binding site and the sensory element. These motifs are in a stretch of approximately 100 amino acid residues in the middle of NS1. These helicases surround DNA as a ring of six or eight subunits with the ATP binding pocket lying between adjacent subunits. The first subunit provides the A and B motifs, and the arginine
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
residue of the second subunit functions as a trans-acting arginine finger sensor for ATP binding and hydrolysis status. The arginine finger lies after the C motif but in three dimensions it is often embedded in a cluster of positively charged amino acids. In a ring configuration this domain interacts with the ATP binding pocket of the neighboring subunit.
NS1 binds to both the left and right hand origins of replication on the right with the host's own high mobility group
High mobility group
High-Mobility Group or HMG is a group of chromosomal proteins that help withtranscription, replication, recombination, and DNA repair.-Families:The HMG proteins are subdivided into 3 superfamilies each containing a characteristic functional domain:...
proteins and on the left with glucocorticoid
Glucocorticoid
Glucocorticoids are a class of steroid hormones that bind to the glucocorticoid receptor , which is present in almost every vertebrate animal cell...
modulatory element-binding proteins. Origin recognition leads to strand- and site-specific nicking of viral DNA, processes that require ATP for tight binding and subsequent nicking. The NS1 protein remains covalently linked to the 5′ end of nicked DNA with the 3′-hydroxyl group being used for synthesis of the nascent strand. Replication of the genome is thought to be mediated by DNA polymerase
DNA polymerase
A DNA polymerase is an enzyme that helps catalyze in the polymerization of deoxyribonucleotides into a DNA strand. DNA polymerases are best known for their feedback role in DNA replication, in which the polymerase "reads" an intact DNA strand as a template and uses it to synthesize the new strand....
δ. This polymerase is usually involved in repair of DNA after the excision of nucleotides. This process involves proliferating cell nuclear antigen, the single strand-binding protein replication protein A
Replication protein A
Replication protein A is a protein that binds single-stranded DNA in eukaryotic cells. During DNA replication, RPA prevents single-stranded DNA from winding back on itself or from forming secondary structures. This keeps DNA unwound for the polymerase to replicate it...
and NS1. In this process NS1 acts as an ATP powered helicase to resolve terminal hairpin structures of the viral genome.
In addition to these functions NS1 enhances transcription from a viral capsid promoter, may assist in packing DNA into newly formed capsids and is responsible for the cytopathic effect of parvoviruses.
Genetics
There is 78%, 67%, and 80% identity between Human Bocavirus 1 and 2 NS1, NP1, and VP1/VP2 proteins respectively.There are four genotypes from humans of this virus are known - type 1 to 4. Types 1 and 2 appear to have diverged recently (circa 1985) Recombination may occur between strains. The estimated mean evolutionary rate is 8.6 x 10(-4) substitutions/site/year. The 1st + 2nd codon positions evolve 15 times more slowly than those of the 3rd codon position.
Phylogenetic analysis of this genus groups the swine bocavirus with canine minute virus.
Bocaviruses have been isolated from pigs
Human bocavirus 3 appears to be a recombinant of human bocavirus 1 and human bocavirus 2 and 4.
Incomplete sequences of bocaviruses have been obtained from wild chimpanzees. These sequences phlyogenetically lie within the known human bocavirus isolates but also show evidence of recombination.
Clinical
HBoV is found rarely in respiratory samples from healthy subjects. In patients with respiratory complaints, it can be found alone or, more often, in combination with other viruses known to cause respiratory complaints.Newborns are probably protected by passive immunisation.
The age group most frequently affected appear to be children between the ages of six months to two years, although cases in children older than five and even in a 28-year-old have been reported.
HBoV can be detected not only in respiratory samples but also in blood, urine and stools. The latter two may merely reflect viral shedding, although diarrhoea has been described in animal bocaviral infections, and some patients with HBoV seem to have diarrhoea independent of respiratory symptoms.
A study in Jordan found that 9% of 220 children hospitalised with lower respiratory tract infection were infected with bocavirus. Of those infeced the median age was 4 months. Coughing (100%), wheezing (82.7%) and fever (68.2%) were the most common clinical findings with bronchopneumonia (35%) and bronchiolitis (30%) being the most common ultimate diagnoses.
HBoV1 has been generally associated with respiratory symptoms while other HBoV tend to be associated with diarrhea and acute flaccid paralysis.