Review Human Bocaviruses and Paediatric Infections
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Review Human bocaviruses and paediatric infections Andreas Christensen, Olli Kesti, Varpu Elenius, Anna L Eskola, Henrik Døllner, Can Altunbulakli, Cezmi A Akdis, Maria Söderlund-Venermo, Tuomas Jartti Human bocavirus 1 (HBoV1), belonging to the Parvoviridae family, was discovered in 2005, in nasopharyngeal Lancet Child Adolesc Health 2019 samples from children with respiratory tract infections. Three additional bocaviruses, HBoV2–4, were discovered in Published Online 2009–10. These viruses have mainly been found in faecal samples and their role in human diseases is still uncertain. April 1, 2019 HBoV1 causes a wide spectrum of respiratory diseases in children, including common cold, acute otitis media, http://dx.doi.org/10.1016/ S2352-4642(19)30057-4 pneumonia, bronchiolitis, and asthma exacerbations. HBoV1 DNA can persist in airway secretions for months after Department of Medical an acute infection. Consequently, acute HBoV1 infection cannot be diagnosed with standard DNA PCR; quantitative Microbiology PCR and serology are better diagnostic approaches. Because of their high clinical specificity, diagnostic developments (A Christensen MD) and such as HBoV1 mRNA and antigen detection have shown promising results. This Review summarises the knowledge Department of Pediatrics on human bocaviruses, with a special focus on HBoV1. (H Døllner MD), St Olavs Hospital, Trondheim, Norway; Department of Clinical and Introduction overview of the knowledge regarding human bocaviruses Molecular Medicine, Human bocavirus 1 (HBoV1) was discovered in 2005, in with an emphasis on clinical features and diagnostic Norwegian University of nasopharyngeal aspirates from children with respiratory implications. The epidemiology, basic virology, and Science and Technology, Trondheim, Norway tract infections, and belongs to the Parvoviridae family. pathogenesis of bocaviruses are briefly discussed. (A Christensen, H Døllner); The closest relatives to HBoV1 are found in animals, Department of Paediatrics, whereas the well known human parvovirus B19 is more Virus genome and structure Turku University Hospital and distantly related.1 Accumulating evidence, since 2005, has Parvoviruses are small (approximately 25 nm) non-en- University of Turku, Turku, Finland (O Kesti, V Elenius MD, been obtained in support of HBoV1 being a genuine veloped viruses, with icosahedral T=1 capsid symmetry T Jartti MD); Department of human pathogen causing mild to severe respiratory tract and a linear single-stranded DNA genome of 4–6 kb in Education, University of Turku, infections in children.2–13 Because of the absence of length, with palindromic hairpin structures at both ends. Turku, Finland (A L Eskola MA); Swiss Institute of Allergy and animal models for HBoV1 infection, the evidence is One full-length HBoV1 genome (including hairpin ends) Asthma Research, University of mainly epidemiological and clinical, including both case- has been sequenced and is 5543 nucleotides (nt) long Zürich and Christine Kühne- control and longitudinal studies that use stringent with non-identical terminal hairpins of 140 nt and 122 nt Center for Allergy Research and diagnostic criteria based on serology, quantitative PCR, (GenBank number JQ923422).28 Most of the encapsidated Education, Davos, Switzerland 14 29 (Prof C A Akdis MD, HBoV1 monoinfection, or HBoV1 mRNA detection. HBoV1 DNA strands have a negative polarity. C Altunbulakli PhD); and HBoV1 can be detected in airway samples from up to a The HBoV1 genome contains two main reading frames, Department of Virology, quarter of children with upper or lower respiratory tract the left (3ʹ) half of the negative-strand genome encoding University of Helsinki, Helsinki, infections (appendix). the non-structural NS1–4 proteins, and the right (5ʹ) half Finland (M Söderlund-Venermo PhD) Since 2009, three additional bocaviruses designated encoding the structural capsid proteins VP1–3, where 15–17 14,30–33 Correspondence to: HBoV2–4 have been discovrered. These viruses have VP3 is the major capsid protein (figure 1). Unlike Dr Andreas Christensen, mainly been detected in faecal samples with detection other parvoviruses, bocaviruses also have a smaller third Department of Medical ranging from 1% to more than 40% in children both with middle reading frame encoding a unique nuclear protein, Microbiology, St Olavs Hospital, and without gastrointestinal illnesses (appendix). HBoV NP1, important in viral DNA replication and mRNA 7006 Trondheim, Norway 34,35 andreas.christensen@stolav. DNA has also been detected in serum, cerebrospinal processing. HBoV1 has been shown to express a 140 nt no fluid, urine, tonsillar tissue, tumour tissue, and even in non-coding RNA (Boca SR) at the right-hand side of the See Online for appendix sewage and river water.2,18–24 Clinical implications of these negative-sense genome that is required for NS protein non-respiratory findings are uncertain. expression.36 Intraspecies recombination has been shown From a clinical perspective, HBoV1 seems to be the most important of the human bocaviruses and should be part of a standard test repertoire for respiratory tract Key messages infections in children admitted to hospital. However, • Human bocaviruses (HBoVs) are common in humans detection of HBoV1 DNA in nasopharyngeal aspirates • Four types of designated HBoV have been described— from healthy children is also common, which leads to HBoV1–4 a low clinical specificity for the widely used HBoV1 • HBoV1 is associated with respiratory tract infections in 2,7,13,25 DNA PCR method. Therefore, accurate diagnosis children of HBoV1 infections should not be based on qualitative • HBoV2–4 are mainly detected in faecal samples and their PCR alone. During the past 10 years, improved diagnostic pathogenic potential is uncertain approaches based on serology, quantitative DNA analysis, • HBoV1 infection should not be diagnosed on the basis of mRNA detection, and antigen detection have been HBoV1 DNA detection alone 2,8,11,12,26,27 developed. Despite the high prevalence of • Quantitative HBoV1 DNA analysis, serology, or HBoV1 paediatric HBoV1 infections, the virus is still not mRNA detection are recommended diagnostic approaches recognised by many clinicians. In this Review, we give an www.thelancet.com/child-adolescent Published online April 1, 2019 http://dx.doi.org/10.1016/S2352-4642(19)30057-4 1 Review 3' P5 5' throughout the year, and no clear seasonality has been observed in epidemi ological studies that controlled for 7,13 NP1 Boca SR sampling frequency. In adults with respiratory illness, HBoV1 has been detected in less than 10% of cases, and NS1 VP1–3 in most studies, in less than 1% of cases (appendix). NS1–70 HBoV2–4 DNA has been detected mainly in faecal samples (appendix). However, the prevalence of human NS2 bocaviruses in patients without diarrhoea is similar 44 Reading frames to that in patients with gastrointestinal diseases. NS3 1 Import antly, HBoV2 DNA has been shown to be present 2 in faecal samples for months, possibly explaining the NS4 3 similar prevalence.8 HBoV1 has also been detected in faeces, presumably representing the intestinal passage Figure 1: Human bocavirus 1 genome structure The 5543 nucleotide human bocavirus 1 linear negative-sense single-stranded DNA genome with hairpin termini of the viruses secreted from the respiratory tract in is depicted as a black line, with the P5 promoter represented as a black arrow. Below the genome, open reading children either with or without accompanying respiratory frames are depicted in blue and red boxes for the non-structural (NS1–4 and NP1) genes and in green for the symptoms.44 overlapping structural (VP1–3) genes, expressed in a ratio of 1:1:10. The non-coding RNA (Boca SR) is depicted The prevalence of acute HBoV1 infections could only be in red. Spliced introns are indicated as thin lines. determined after the development of serodiagnosis. In one study, maternal antibodies were shown to be present for all four human bocaviruses,17 and a recombination in 90% of children younger than 3 months old, after event between HBoV1 and a common ancestor of HBoV2 which seropositivity decreased, reaching low antibody and HBoV4 might have led to the formation of HBoV3.37 detection when the child was between age 6 months and The HBoV1 capsid follows the typical parvovirus struct- 12 months.45 After infancy, HBoV sero prevalence ure comprising 60 copies of the major capsid protein increases until age 6 years, by which time 90–100% of motif. The capsid structure has been determined to children have circulating antibodies against at least one of 2·9 Å resolution by cryo-electron microscopy and three the four human bocaviruses.8,46 HBoV1 IgG antibody dimensional image reconstruction.38 The inner core of the concentrations remain high during adulthood, probably capsid is formed by an α-helix and an eight-stranded because of the immunity boost caused by circulating β-barrel structure, typical of parvoviruses.39 Long amino HBoV1 or by an infection of related HBoV2, HBoV3, or acid loops between the β-strands shape the surface of the both.8,9,46,47 Antibody cross-react ivity can occur between the capsid. Some features of this topology are shared with different bocaviruses, but this problem can be overcome many other parvoviruses, including an open channel at the by blocking the antibodies recognising common epitopes 5-fold axes with a surrounding depression, another by a competition enzyme immuno- assay.8,46 At age 6 years, depression at the 2-fold axes, and protrusions at the 3-fold the seroprevalence of HBoV1 is already around 80%, for axes. The 5-fold channel is used for externalisation of HBoV2 it is 50%, for HBoV3 10%, and for HBoV4 it is VP1u, packaging, and uncoating of viral DNA. HBoV1- close to zero, when cross reactivity is controlled for.8,46 specific variable-loop regions, which are important for However, immunlogical so-called original antigenic sin infectivity and antigenicity, have also been identified on results in further complication by giving an underestimate the capsid.38 The viral capsid surface is involved in many of the seroprevalence.