Human bocavirus

Not to be confused with Bornavirus or Bocas virus, a Coronavirus.
Human bocavirus
Virus classification
Group: Group II (ssDNA)
Order: Unassigned
Family: Parvoviridae
Subfamily: Parvovirinae
Genus: Bocaparvovirus
Species
  • Primate bocaparvovirus 1
  • Primate bocaparvovirus 2

Human bocavirus (HBoV) is a parvovirus that has been suggested to cause human disease. It is a probable cause of lower respiratory tract infections and it has been linked to gastroenteritis, although the role of this emerging infectious disease in human disease has not been firmly established. The term human bocavirus can refer to any bocaparvovirus strain in the Primate bocaparvovirus 1 and Primate bocaparvovirus 2 species that infects humans.

History

Allander and colleagues at the Karolinska Institutet 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).[1] 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)[2] and WU (Washington University),[3] 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,[4][5] behind rhinoviruses, respiratory syncytial virus and adenoviruses.[6]

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.[7] 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.

Virology

The virons 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.[8]

The HBoV capsid shares three characteristic features also found in the other vertebrate parvoviruses:[8] (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 5.5 kilobases in length with terminal hairpin structures at both ends.

The genome encodes 3 open reading frames (ORF1, 2 and 3). The left ORF encodes 4 non structural proteins (NS1, NS2, NS3 and NS4). The middle ORF encodes NP1. The right hand ORF (ORF3) encodes the capsid proteins (VP1, VP2, and VP3). The NP1 gene is in an alternate reading frame to VP1 and overlaps the start of VP1 by 13 nucleotides. Similarly, VP3 is collinear to VP1 and VP2 and results from initiation of translation at a downstream ATG and co-terminates. VP2 is translated from a non-canonical start codon GUG.

NP1 is a small non-structural protein that could induce apoptosis in transfection of HeLa cells.[9]

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) mRNAs.[10] The poly A tail is about 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.[11] Replication results in the creation of a series of circular head to tail sequences.[12]

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.[13] unlike other parvoviruses where this has been examined.

The receptor for bovine parvovirus 1 is sialic acid.

Molecular biology

NS1 belongs to the superfamily III (SF3) helicases 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.

Genetics

There is 78%, 67%, and 80% identity between Human Bocavirus 1 and 2 NS1, NP1, and VP1/VP2 proteins respectively.[14]

There are four known human genotypes of this virus: type 1 to 4. Types 1 and 2 appear to have diverged recently (circa 1985)[15] Recombination may occur between strains. The estimated mean evolutionary rate is 8.6×10−4 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.[16]

Bocaviruses have been isolated from pigs[17]

Human bocavirus 3 appears to be a recombinant of human bocavirus 1 and human bocavirus 2 and 4.[18]

Incomplete sequences of bocaviruses have been obtained from wild chimpanzees.[19] These sequences phylogenetically lie within the known human bocavirus isolates but also show evidence of recombination.

Clinical

Chest radiograph of a 16-month-old boy in Finland with human bocavirus 1 pneumonia, on day 2 of hospitalization. Bilateral pulmonary infiltrations and atelectasis of the upper right lobe can be seen.

HBoV is found in respiratory samples from healthy subjects.[20] In patients with respiratory complaints, it can be found alone or, more often, in combination with other viruses known to cause respiratory complaints.[4] Newborns are probably protected by passive immunisation.[21] The age group most frequently affected appear to be children between the ages of six months to two years,[21][22] although cases in children older than five and even in a 28-year-old have been reported.[23]

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.[24][25]

A study in Jordan found that 9% of 220 children hospitalised with lower respiratory tract infection were infected with bocavirus.[26] Of those infected 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.

Although most cases are mild, severe respiratory disease has also been reported.[27]

Life-threatening infection caused by human bocavirus was described in previously healthy 20-months old prematurely born child.[28]

References

  1. ↑ Allander T, Tammi MT, Eriksson M, Bjerkner A, Tiveljung-Lindell A, Andersson B (September 2005). "Cloning of a human parvovirus by molecular screening of respiratory tract samples". Proc. Natl. Acad. Sci. U.S.A. 102 (36): 12891–6. doi:10.1073/pnas.0504666102. PMC 1200281Freely accessible. PMID 16118271.
  2. ↑ Allander T, Andreasson K, Gupta S, et al. (2007). "Identification of a third human polyomavirus". J. Virol. 81 (8): 4130–6. doi:10.1128/JVI.00028-07. PMC 1866148Freely accessible. PMID 17287263. Retrieved 2008-01-18.
  3. ↑ Gaynor AM, Nissen MD, Whiley DM, et al. (2007). "Identification of a novel polyomavirus from patients with acute respiratory tract infections". PLoS Pathog. 3 (5): e64. doi:10.1371/journal.ppat.0030064. PMC 1864993Freely accessible. PMID 17480120. Retrieved 2008-01-18.
  4. 1 2 Ricour C, Goubau P (2008). "Human bocavirus, a newly discovered parvovirus of the respiratory tract". Acta Clin Belg. 63 (5): 329–34. doi:10.1179/acb.2008.064. PMID 19186566.
  5. ↑ Allander T, Jartti T, Gupta S, et al. (April 2007). "Human bocavirus and acute wheezing in children". Clin. Infect. Dis. 44 (7): 904–10. doi:10.1086/512196. PMID 17342639.
  6. ↑ Pozo F, García-García ML, Calvo C, Cuesta I, Pérez-Breña P, Casas I (November 2007). "High incidence of human bocavirus infection in children in Spain". J. Clin. Virol. 40 (3): 224–8. doi:10.1016/j.jcv.2007.08.010. PMID 17904416.
  7. ↑ Schwartz D, Green B, Carmichael LE, Parrish CR (October 2002). "The canine minute virus (minute virus of canines) is a distinct parvovirus that is most similar to bovine parvovirus". Virology. 302 (2): 219–23. doi:10.1006/viro.2002.1674. PMID 12441065.
  8. 1 2 Gurda BL, Parent KN, Bladek H, Sinkovits RS, DiMattia MA, Rence C, Castro A, McKenna R, Olson N, Brown K, Baker TS, Agbandje-McKenna M (2010). "Human bocavirus capsid structure: insights into the structural repertoire of the parvoviridae". J. Virol. 84 (12): 5880–9. doi:10.1128/JVI.02719-09. PMC 2876641Freely accessible. PMID 20375175.
  9. ↑ Sun B, Cai Y, Li Y, Li J, Liu K, Li Y, Yang Y (2013). "The nonstructural protein NP1 of human bocavirus 1 induces cell cycle arrest and apoptosis in Hela cells". Virology. 440 (1): 75–83. doi:10.1016/j.virol.2013.02.013. PMID 23507451.
  10. ↑ Qiu J, Cheng F, Johnson FB, Pintel D (2007). "The transcription profile of the bocavirus bovine parvovirus is unlike those of previously characterized parvoviruses". J. Virol. 81 (21): 12080–5. doi:10.1128/JVI.00815-07. PMC 2168810Freely accessible. PMID 17715221.
  11. ↑ Tattersall P, Ward DC (1976). "Rolling hairpin model for replication of parvovirus and linear chromosomal DNA". Nature. 263 (5573): 106–9. doi:10.1038/263106a0. PMID 967244.
  12. ↑ Zhao H, Zhao L, Sun Y, Qian Y, Liu L, Jia L, Zhang Y, Dong H (2012). "Detection of a bocavirus circular genome in fecal specimens from children with acute diarrhea in Beijing, China". PLoS ONE. 7 (11): e48980. doi:10.1371/journal.pone.0048980. PMC 3487788Freely accessible. PMID 23133667.
  13. ↑ Chen AY, Cheng F, Lou S, Luo Y, Liu Z, Delwart E, Pintel D, Qiu J (2010). "Characterization of the gene expression profile of human bocavirus". Virology. 403 (2): 145–54. doi:10.1016/j.virol.2010.04.014. PMC 2879452Freely accessible. PMID 20457462.
  14. ↑ Kapoor A, Slikas E, Simmonds P, Chieochansin T, Naeem A, Shaukat S, Alam MM, Sharif S, Angez M, Zaidi S, Delwart E (2009). "A newly identified bocavirus species in human stool". J. Infect. Dis. 199 (2): 196–200. doi:10.1086/595831. PMC 2678954Freely accessible. PMID 19072716.
  15. ↑ Zehender G, De Maddalena C, Canuti M, Zappa A, Amendola A, Lai A, Galli M, Tanzi E (2010). "Rapid molecular evolution of human bocavirus revealed by Bayesian coalescent inference". Infect. Genet. Evol. 10 (2): 215–20. doi:10.1016/j.meegid.2009.11.011. PMID 19932194.
  16. ↑ Zeng S, Wang D, Fang L, Ma J, Song T, Zhang R, Chen H, Xiao S (2011). "Complete coding sequences and phylogenetic analysis of porcine bocavirus". J. Gen. Virol. 92 (Pt 4): 784–8. doi:10.1099/vir.0.028340-0. PMID 21228124.
  17. ↑ Lau SK, Woo PC, Yip CC, Li KS, Fu CT, Huang Y, Chan KH, Yuen KY (2011). "Co-existence of multiple strains of two novel porcine bocaviruses in the same pig, a previously undescribed phenomenon in members of the family Parvoviridae, and evidence for inter- and intra-host genetic diversity and recombination". J. Gen. Virol. 92 (Pt 9): 2047–59. doi:10.1099/vir.0.033688-0. PMID 21632566.
  18. ↑ Cheng W, Chen J, Xu Z, Yu J, Huang C, Jin M, Li H, Zhang M, Jin Y, Duan ZJ (2011). "Phylogenetic and recombination analysis of human bocavirus 2". BMC Infect. Dis. 11: 50. doi:10.1186/1471-2334-11-50. PMC 3056791Freely accessible. PMID 21345238.
  19. ↑ Sharp CP, LeBreton M, Kantola K, Nana A, Diffo Jle D, Djoko CF, Tamoufe U, Kiyang JA, Babila TG, Ngole EM, Pybus OG, Delwart E, Delaporte E, Peeters M, Soderlund-Venermo M, Hedman K, Wolfe ND, Simmonds P (2010). "Widespread infection with homologues of human parvoviruses B19, PARV4, and human bocavirus of chimpanzees and gorillas in the wild". J. Virol. 84 (19): 10289–96. doi:10.1128/JVI.01304-10. PMC 2937811Freely accessible. PMID 20668071.
  20. ↑ Fry AM, Lu X, Chittaganpitch M, et al. (April 2007). "Human bocavirus: a novel parvovirus epidemiologically associated with pneumonia requiring hospitalization in Thailand". J. Infect. Dis. 195 (7): 1038–45. doi:10.1086/512163. PMID 17330795.
  21. 1 2 Ma X, Endo R, Ishiguro N, et al. (March 2006). "Detection of human bocavirus in Japanese children with lower respiratory tract infections". J. Clin. Microbiol. 44 (3): 1132–4. doi:10.1128/JCM.44.3.1132-1134.2006. PMC 1393160Freely accessible. PMID 16517912.
  22. ↑ Endo R, Ishiguro N, Kikuta H, et al. (October 2007). "Seroepidemiology of human bocavirus in Hokkaido prefecture, Japan". J. Clin. Microbiol. 45 (10): 3218–23. doi:10.1128/JCM.02140-06. PMC 2045318Freely accessible. PMID 17699639.
  23. ↑ Kupfer B, Vehreschild J, Cornely O, et al. (October 2006). "Severe pneumonia and human bocavirus in adult". Emerging Infect. Dis. 12 (10): 1614–6. doi:10.3201/eid1210.060520. PMC 3290954Freely accessible. PMID 17176591.
  24. ↑ Lau SK, Yip CC, Que TL, et al. (October 2007). "Clinical and molecular epidemiology of human bocavirus in respiratory and fecal samples from children in Hong Kong". J. Infect. Dis. 196 (7): 986–93. doi:10.1086/521310. PMID 17763318.
  25. ↑ Vicente D, Cilla G, Montes M, Pérez-Yarza EG, Pérez-Trallero E (April 2007). "Human bocavirus, a respiratory and enteric virus". Emerging Infect. Dis. 13 (4): 636–7. doi:10.3201/eid1304.061501. PMC 2725986Freely accessible. PMID 17553287.
  26. ↑ Al-Rousan HO, Meqdam MM, Alkhateeb A, Al-Shorman A, Qaisy LM, Al-Moqbel MS (2011). "Human bocavirus in Jordan: prevalence and clinical symptoms in hospitalised paediatric patients and molecular virus characterisation" (PDF). Singapore Med J. 52 (5): 365–9. PMID 21633772.
  27. ↑ Edner N, Castillo-Rodas P, Falk L, Hedman K, Söderlund-Venermo M, Allander T (2012). "Life-threatening respiratory tract disease with human bocavirus-1 infection in a 4-year-old child". J. Clin. Microbiol. 50 (2): 531–2. doi:10.1128/JCM.05706-11. PMC 3264148Freely accessible. PMID 22135260.
  28. ↑ Ursic T, Steyer A, Kopriva S, Kalan G, Krivec U, Petrovec M (2011). "Human bocavirus as the cause of a life-threatening infection". J. Clin. Microbiol. 49 (3): 1179–81. doi:10.1128/JCM.02362-10. PMC 3067724Freely accessible. PMID 21227992.

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