key: cord-0977665-mg7k1pt8
authors: Schildgen, O.; Schildgen, V.
title: Respiratory infections of the human bocavirus
date: 2016-08-05
journal: The Microbiology of Respiratory System Infections
DOI: 10.1016/b978-0-12-804543-5.00005-1
sha: 0b71c286d446269acaefbfa63e64125241ed3efb
doc_id: 977665
cord_uid: mg7k1pt8

The human bocavirus is one of the most common respiratory viruses and occurs in all age groups. It is associated with upper and lower respiratory tract infections, and causes clinical symptoms from the mild common cold to life threatening respiratory diseases. Besides its ability to persist the virus appears to trigger chronic lung disease and increase the clinical symptoms, while being a putative trigger for fibrotic lung diseases. Laboratory diagnostics should include serological diagnostics in order to rule out a viremia because due to prolonged viral shedding acute and chronic infections cannot be differentiated on the detection of viral nucleic acids in respiratory specimen alone. Although Koch’s postulates cannot be formally fulfilled due to the lack of an animal model and the chance for clinical trials with volunteers are limited due to the long term effects of HBoV infections, there is no doubt that the virus is a serious pathogen and requires attention. The aim of the chapter is to present an overview of our current knowledge on respiratory infections with the human bocavirus, and to provide basic and essential information on clinical features, molecular diagnostics, and epidemiologic challenges arising with this pathogen.

The human bocavirus (HBoV) was initially discovered in clinical samples from the respiratory tract of children suffering from respiratory infections of unknown etiology. 1 To date, HBoV is the fourth most detected respiratory virus, but as there is still no animal model or a broadly convertible cell culture available, Koch's modified postulates have not yet been completely fulfilled. 3 Nevertheless, HBoV is the second parvovirus that is capable of infecting humans with the potential to cause clinical disease. Until HBoV was discovered, parvovirus B19 was the sole human parvovirus, which can hardly be cultured in in vitro cell cultures, likely because it strongly depends on the optimal cell cycle phase. [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] This latter fact hampered the development of potent and specific antivirals, tenacity studies, and the development of disinfectants active against human parvoviruses as surrogate pathogens with animal pathogenicity were used. The discovery of HBoV led to a couple of molecular findings that are of major general interest for the human parvovirus biology and clinics. Within a primary cell culture that productively replicated the human bocavirus, it was possible 5 to identify the HBoV transcriptome, including the splicing variant of viral RNA. 14 This cell culture displayed for the first time a tool for the investigation of a human parvovirus in its natural infectious surrounding enabling follow up studies on the molecular biology of human parvoviruses in general, and HBoV in particular.

Unfortunately, the primary cell culture that enables HBoV growth in vitro is very expensive, requires a highly specialized laboratory, and is an error-prone cell culture, thus the availability of this technology is rather limited to a couple of laboratories worldwide, which in turn is a stumbling block for further research. In search for a broadly convertible replication system the group of Jianming Qiu from Kansas made a significant step forward: by establishing a plasmid based repliconlike system the group identified additional RNA species that are transcribed during the HBoV replication cycle. 15 The system is based on plasmids that contain the complete published HBoV sequence but are flanked by ITR-regions of the adeno-associated virus (AAV); the ITR-regions are terminal repeats containing palindromic sequences that form hairpin-like structures, which in turn are required for the replication of parvoviruses according to the so-called rolling hairpin mechanisms of replication. 16 Although the hairpin-like structures of HBoV had yet not been described at that time, it was postulated that also the HBoV genome is flanked by such structures and that HBoV replicates its genome by the rolling hairpin mechanism, although this assumption is exclusively based on phylogenetic analogous conclusion rather than on experimental evidence. In theory, the rolling hairpin replication results in progeny genomes that occur in equal amounts of both polarities, while packaging of viral genomes is dependent on additional factors. [17] [18] [19] [20] [21] [22] [23] For almost four decades, it was postulated that all parvoviruses replicate according to this mechanism, although this replication model is solely based on experimental data obtained by the research on rodent parvoviruses. The model is characterized by a terminal hairpin dependent self-priming initiation of the viral genome replication and concatemeric replication intermediates of head-to-head or tail-to-tail replication intermediates. Based on an early publication of the postulated model in 1976 in Nature, this replication model became a dogma in the field of parvovirology and was deemed to be true for all parvoviruses. Interestingly, it was impossible to identify both genome polarities in clinical samples containing HBoV infected cells. 24 Thereby, NASBA analyses revealed that all HBoV strains package negative strand genome while only a minority also package the plus strand; this observation is compatible with another replication mechanism, known as rolling circle replication. A couple of systematic PCR-based analyses were performed to test the hypothesis if rolling circle replication may occur in HBoV infection and to decipher the unknown terminal hairpins. 25 This approach identified DNA sequences that contained head-to-tail genome fragments linked by a newly identified linker stretch that had a partial by high homology to the minute virus of canine (MVC) ITR and to the ITR of bovine parvovirus. Most recently, it was shown that these sequences most likely represent the missing terminal hairpin like structures, 25, 26 and it is likely that the virus was originally transmitted as a zoonosis (Fig. 5.1 ). Despite identifying the terminal sequences in clinical samples and also in cell cultures, not only a lack of self-priming activity of HBoV-genomes but also the lack of intermediates typical for rolling hairpin replication were observed. Instead, the samples contained head-to-tail structures. Several groups published similar observations, all tackling the dogma of parvovirus replication. [27] [28] [29] [30] It is therefore important to know that the head-to-tail episomal form of HBoV differs from formerly described circular parvoviral episomes that have been shown to consist of circular closed genome dimers of head-to-head and tail-to-tail orientation. 31 Although the role of the linker sequence and the head-to-tail junction remains unclear, these findings were surprising as they support the hypothesis that HBoV replicates differently from nonhuman parvoviruses by possibly initiating a rolling circle mechanism, at least as an alternative route of replication.

Based on the newly identified sequences, the structure of the putative terminal repeats of the HBoV genome were predicted in silico. 26 Beyond that, the Kansas group developed a true full-length vector clone of HBoV which can be transfected to HEK-293 cells and produces a "recombinant wild type" human bocavirus that in turn is infectious for differentiated CuFi-8 cells. 32 CuFi-8 cells are derived from a patient with cystic fibrosis and can be grown as monolayer cultures that by change of the culturing media can be differentiated into a polarized respiratory epithelial structure that in turn supports HBoV replication. 32 This novel cell culture gives raise to the hypothesis that HBoV is a true serious pathogen because it induced a remarkable cytopathic effect in the polarized CuFi-8 cell line, which in turn is compatible with the assumption that clinical symptoms of an HBoV infection are caused by tissue

Based on sequence analyses, especially of the terminal sequences, a zoonotic event is likely, as HBoV-1 contains genome structures highly conserved from the canine minute virus and the bovine parvovirus. damages due to the viral replication. Thereby, this infection model harbors a surprising feature that is a further hint for an alternative replication of the human bocavirus-if the full-length HBoV plasmid containing the hairpin sequences is transfected into HEK293 cells, then infectious progeny virions are produced, although based on the rolling hairpin model this process must be impossible because the free (!) hairpin sequences are believed to be essential for the replication. In contrast, in the plasmid they are flanked by the vector's backbone sequence, replication is possible although no helper plasmids are required as known for the dependoviruses. This simple observation strongly contradicts the model of rolling hairpin replication but in turn favours other replication models known for circular DNA, for example the rolling circle replication, which in the natural infection would produce head-to-tail concatemers.

Furthermore, clinical observations give raise to the hypothesis that the HBoV replication can be triggered or influenced by human herpesviruses, such as HHV-6, CMV, and Herpes simplex Virus. In this context, it is noteworthy that herpesviruses, especially HSV, are capable of initiating a rolling circle replication mechanism of replication in trans, as shown for SV40, which has a circular double stranded genome. 33 Thereby, herpesviruses may either act as a trigger that arrests the host cell at transition from G1-to S-phase of the cell cycle or they could directly interact with the HBoV DNA supporting the replication by the herpesviral replication enzymes. The latter appears likely because head-to-tail intermediates are a feature of the rolling circle replication that may be initiated by a couple of viruses including the human herpesviruses type 1 and type 6. [33] [34] [35] [36] [37] [38] [39] [40] These viruses (eg, AAV) in turn are able to act as helper viruses for the parvoviral subclass dependoviruses, that require those helper viruses for their replication. [36] [37] [38] [39] [40] Recently, a clinical case was observed in which the HBoV infection appeared to depend on coinfection and coreplication of human herpesvirus type 6. In this case, the HBoV infection persisted because of an immune disease but was terminated by antiviral therapy with cidofovir which is directed against HHV6. 41 This was the key observation leading to the assumption that HBoV is either sensitive to cidofovir or that a possible rolling circle HBoV replication is triggered by HHV6, which in turn would explain the high frequency of coinfections observed in case of HBoV. 40, 42, 43 In 2011, two severe cases of respiratory failure in adults associated with HBoV infection, herpesvirus coinfection, and a history of lung fibrosis likely dedicated to the presence of chronic HBoV infection 44 indicate that the head-to-tail structures could have been episomal reservoirs enabling the virus' persistence as postulated by Kapoor and coworkers. 27 It may be speculated whether the persistence of HBoV episomes in the lung of the patients in analogy to a HBV infection, in which episomal cccDNA persists in the infected cell until the cell is targeted by the immune response or subjected to apoptosis, and in which this chronic state frequently goes ahead with a mild inflammation that is subclinical but finally could induce fibrosis, could have led to mild chronic inflammation eventually resulting in fibrosis of the lung, which could not be easily compensated as in the liver. In the context of a putative chronic HBoV infection or a persistence of HBoV at a subclinical level, it thus appears possible that HBoV could directly or indirectly, by interactions with the immune system, contribute to chronic lung disease such as idiopathic lung fibrosis.

Another recently detected novel feature of HBoV is the expression of more nonstructural proteins than concluded from our previous knowledge on parvovirus replication studies. Shen et al. have shown that besides NS1 three novel proteins named NS2, NS3, and NS4, are expressed during the viral replication, of which NS2 is believed to have a crucial role during the viral life cycle. 45 

Like all respiratory pathogens (except SARS-and MERS-coronavirus) that cause respiratory infections, HBoV-1 is distributed worldwide and has been detected in patients from several regions of each continent. However, unlike most other viruses that are known to peak seasonally in autumn and winter, HBoV infection peaks do not seem to be restricted to these seasons.

Although the route of transmission has not yet been systematically investigated, it is widely accepted that the transmission of HBoV most likely occurs by smear, or droplet infections or aerosols, and nasal or oral uptake, as described for the majority of "common cold viruses." The transmission route passes through airway excretions but could also happen via the gastrointestinal route, as HBoV is also shedded by stool (Fig. 5.2) .

The HBoV seroprevalence is high and reached 95%, and more in children up to the age of 5 years. 99, 100 This seroprevalence remains high in most adults, 62,68 but decreases from 96% to 59% in European adults if antibodies against HBoV strains 2-4 were depleted. Thus, in 41% of patients no long term immunity could be generated, supporting the assumption that the virus is able to persist and could also reinfect elderly patients. 101 Surprisingly, HBoV-1 DNA can also be detected in blood and blood products from healthy Chinese blood donors with a lower seropositivity compared to the afore mentioned cohorts. 102 

The HBoV-1 infection is clinically indistinguishable from other respiratory infections and can solely be proven by molecular assays. The spectrum of HBoV infections ranges from asymptomatic 53, 103, 104 to mild upper respiratory infections 53,105-107 up to serious and life threatening lower respiratory tract infections 56, 95, [108] [109] [110] [111] [112] [113] [114] [115] [116] [117] [118] in all age groups. 56, 57, 95, 104, [108] [109] [110] [111] [112] [113] [114] [115] [116] [117] [118] [119] [120] [121] The immune response against HBoV starts with an IgM response followed by the formation of IgG, 99,100 but no life long immunity is generated in at least 40% of patients due to the original antigenic sin. 62, 68, 122 HBoV-1 is able to infect the central nervous system 82, 84 and it has been identified as a putative cause of idiopathic lung fibrosis 44 supported by the fact that a set of profibrotic cytokines were upregulated during HBoV infection in adults and their HBoV dependent upregulation was confirmed in cell culture. 123, 124 Whereas, HBoV does not induce a clear Th1 or Th2 response. 125 Furthermore, the HBoV dependent regulated cytokines include a subset of cytokines which are known to be involved in several cancer-associated pathways, supporting the hypothesis that HBoV may be associated with long term diseases or even cancerogenesis. [126] [127] [128] Although this hypothesis requires further prospective studies, HBoV DNA was detected in lung-and colorectal tumors. Detection of HBoV DNA, eventually combined with persistence, was described besides detection in normal lung tissue, 104 and in lung-and colorectal tumors, 128 in other tissues such as, tonsils, 27,129-131 and myocardium, and may affect further tissues that have not yet been tested for HBoV-positivity.

Lung fibrosis, especially the idiopathic lung fibrosis (IPF) is characterized by a Th2-type dominated immune response in the affected tissue (as reviewed by: [132] [133] [134] ). The Th2 response in the lung is accompanied by increased expression levels of IL-4, IL-5, IL-10, and IL-13 and is followed by increased levels-besides others-of CCL17 (TARC) and CCL5 (RANTES). Moreover, fibrosis is related to expression of TNF and IL-8, and it is worth mentioning that the neutralization of TARC leads to a reduction of fibrosis in the animal model. 133, 135 In addition, an elevation of the TARC/IP-10 ratio is also characteristic for fibrosis and was previously discussed as a marker for IPF. 136 Moreover, a so far unique follow up case in which the infection/reactivation of HBoV occurred between two episodes of BAL sampling, and in which the fibrosis associated cytokines were expressed in association with the HBoV infection but not before, supports the previously obtained data. This leads to the conclusion, that HBoV colonisation/chronic infection may be at least one trigger that could stimulate airway remodelling. However, it could be argued that in vivo not only the resident airway epithelial cells are involved in the immune response but also additional patient specific factors will contribute to altered profibrotic cytokine profiles. To address this problem, experiments in an air-liquid-interface culture of human airway epithelial cells were performed. These experiments confirmed that the profibrotic cytokines were expressed by the infected cell cultures but were hardly or not at all expressed in mock-infected cells and they reveal that the identified cytokines belong to the initial immune response after HBoV infection (123) .

According to the literature the two HBoV proteins VP2 and NP1 seem to influence the regulation of the Interferon beta pathway but the data appear controversially as VP2 upregulates the pathway 137 while NP1 inhibits the IFN-beta production when overexpressed. 138 

Simultaneously with the discovery of HBoV in 2005, multiplexing methods started to become an accepted diagnostic tool and as a consequence detection of multiple infections, especially in respiratory tract diseases, has become a common phenomenon. 53, [139] [140] [141] [142] [143] Nowadays, multiple infections with up to six pathogens being simultaneously present in a single respiratory sample are frequent 53, [139] [140] [141] [142] [143] [144] and have misled some researchers to the statement that the human bocavirus, also occurring in asymptomatic patients, is a harmless bystander rather than a pathogen. 145, 146 This hypothesis seems to be supported by the fact that for HBoV a formal fulfilment of Koch's modified postulates was not yet possible 147 because no animal model exists so far and also because volunteer transmission trials cannot be recommended based on our current knowledge. 127 On the contrary, although there is a cohort of asymptomatic carriers, 53, 104, 139, 146, 148, 149 several studies have shown that HBoV induces clinical symptoms. 50, 77, 111, 112, 139, [150] [151] [152] [153] [154] [155] [156] The asymptomatic viral shedding is meanwhile believed to originate from a long term shedding after an acute infection or from persisting viruses, 26, 27, 81, 122, [157] [158] [159] [160] most recently confirmed by a long term prospective cohort study. 53, 161 Thereby, it was shown that the rate of asymptomatic HBoV infections is similar to the rate of rhinovirus infections, and no one would doubt that rhinoviruses are true pathogens. 53 Moreover, HBoV induces a serious cytopathic effect in infected cell cultures, which is a typical feature of a pathogen. 14,32,45,157

Besides several published homebrew PCRs and real-time PCRs (as reviewed by 3 ), numerous commercial assays, such as the Luminex RVP-Assay, 104, 162 the Idaho FilmArray, 144, 162 or the RespiFinder assay 104 have been developed and released to the market enabling the detection of HBoV from clinical samples. However, multiplexing solely allows us to detect the viral DNA in a respiratory sample without providing the essential information if an active replicative infection underlies the currently clinical episode requiring laboratory testing. 53 As HBoV can be shedded for longer than 3 months after the acute symptomatic phase, 53 a proper diagnostics of human bocavirus requires the proof of active replication, which can be done either by detection of a viremia in the peripheral blood, 77, 93, 101, 122, [163] [164] [165] [166] [167] or by detection of spliced viral RNA transcripts that were shown to be present exclusively during the active phase of the replication. 168 

There is an increasing body of evidence showing that the human bocavirus is a serious pathogen that on the one hand is associated with acute respiratory infections, sometimes with life threatening complications, and on the other hand also could contribute to long term diseases of the airways resulting in lung carcinoma or lung fibrosis. Therefore, it remains crucial to analyze the long-term effects of HBoV infections to identify the mechanisms of HBoV persistence and to determine the host factors for asymptomatic infections, as well as to test the hypothesis that HBoV could trigger the development of lung cancer and fibrosis. In any cases, the proper diagnostics of HBoV require attention and need to be evaluated regarding its interaction with other respiratory viruses that may simultaneously be detected in clinical episodes.

Cloning of a human parvovirus by molecular screening of respiratory tract samples

Human bocavirus: passenger or pathogen in acute respiratory tract infections?

Human parvovirus B19-induced cell cycle arrest and apoptosis

Human parvovirus B19 induces cell cycle arrest at G(2) phase with accumulation of mitotic cyclins

In vivo accumulation of cyclin A and cellular replication factors in autonomous parvovirus minute virus of mice-associated replication bodies

Cyclin A activates the DNA polymerase delta -dependent elongation machinery in vitro: a parvovirus DNA replication model

The NS1 protein of the autonomous parvovirus minute virus of mice blocks cellular DNA replication: a consequence of lesions to the chromatin?

S-phase-dependent cell cycle disturbances caused by Aleutian mink disease parvovirus

The nonstructural proteins of the autonomous parvovirus minute virus of mice interfere with the cell cycle, inducing accumulation in G2

Influence of adeno-associated virus on adherence and growth properties of normal cells

Interaction of virally coded protein and a cell cycle-regulated cellular protein with the bovine parvovirus left terminus ori

Molecular biology and pathogenicity of human and animal parvoviruses

Human bocavirus can be cultured in differentiated human airway epithelial cells

Characterization of the gene expression profile of human bocavirus

Rolling hairpin model for replication of parvovirus and linear chromosomal DNA

Replication initiator protein NS1 of the parvovirus minute virus of mice binds to modular divergent sites distributed throughout duplex viral DNA

Encapsidation of minute virus of mice DNA: aspects of the translocation mechanism revealed by the structure of partially packaged genomes

Genome packaging sense is controlled by the efficiency of the nick site in the right-end replication origin of parvoviruses minute virus of mice and LuIII

The left-end and right-end origins of minute virus of mice DNA differ in their capacity to direct episomal amplification and integration in vivo

An asymmetric nucleotide in the parvoviral 3' hairpin directs segregation of a single active origin of DNA replication

Asymmetric resolution of a parvovirus palindrome in vitro

In vitro excision and replication of 59 telomeres of minute virus of mice DNA from cloned palindromic concatemer junctions

Novel application for isothermal nucleic acid sequence-based amplification (NASBA)

Detection of head-to-tail DNA sequences of human bocavirus in clinical samples

Genomic features of the human bocaviruses

Bocavirus episome in infected human tissue contains non-identical termini

A novel bocavirus in canine liver

Detection of a bocavirus circular genome in fecal specimens from children with acute diarrhea in beijing, china

Identification and characterization of porcine bocavirus episomes

Genetic fate of recombinant adenoassociated virus vector genomes in muscle

Establishment of a reverse genetics system for studying human bocavirus in human airway epithelia

Herpes simplex virus-induced "rolling circle" amplification of SV40 DNA sequences in a transformed hamster cell line correlates with tandem integration of the SV40 genome

Herpes simplex virus-directed overreplication of chromosomal DNA physically linked to the simian virus 40 integration site of a transformed hamster cell line

Genome replication and progeny virion production of herpes simplex virus type 1 mutants with temperature-sensitive lesions in the origin-binding protein

Definition of herpes simplex virus type 1 helper activities for adeno-associated virus early replication events

Infection with Parvovirus B19 and Herpes viruses in early pregnancy and risk of second trimester miscarriage or very preterm birth

Human parvovirus B19, varicella zoster virus, and human herpesvirus-6 in mesenchymal stem cells of patients with osteoarthritis: analysis with quantitative real-time polymerase chain reaction

Fatal myocarditis associated with acute parvovirus B19 and human herpesvirus 6 coinfection

Human herpesvirus 6 (HHV-6) is a helper virus for adeno-associated virus type 2 (AAV-2) and the AAV-2 rep gene homologue in HHV-6 can mediate AAV-2 DNA replication and regulate gene expression

Does human bocavirus infection depend on helper viruses? A challenging case report

Human herpesvirus-6 and parvovirus B19 infections in children

Herpesviruses provide helper functions for avian adeno-associated parvovirus

Detection of HBoV DNA in idiopathic lung fibrosis

Identification and functional analysis of novel non-structural proteins of human bocavirus 1

Specific viruses detected in nigerian children in association with acute respiratory disease

Novel respiratory virus infections in children

Human bocavirus in Jordan: prevalence and clinical symptoms in hospitalised paediatric patients and molecular virus characterisation

Human Bocavirus infection

Human bocavirus infection in children with acute respiratory tract infection in India

Viral-bacterial co-infection in Australian Indigenous children with acute otitis media

Clinical description of human bocavirus viremia in children with LRTI

Community surveillance of respiratory viruses among families in the Utah Better identification of germs-longitudinal viral epidemiology (BIG-LoVE) study

PCR improves diagnostic yield from lung aspiration in Malawian children with radiologically confirmed pneumonia

Human bocavirus (HBoV) in Thailand: clinical manifestations in a hospitalized pediatric patient and molecular virus characterization

The association of newly identified respiratory viruses with lower respiratory tract infections in Korean children

Evidence of human bocavirus circulating in children and adults

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Simultaneous detection of human bocavirus and adenovirus by multiplex real-time PCR in a Belgian paediatric population

Detection of human bocavirus in hospitalised children

Viral etiologies of acute respiratory infections among hospitalized Vietnamese children in Ho Chi Minh City

Seroepidemiology of human bocavirus in Hokkaido prefecture

Impact of human bocavirus on children and their families

The prevalence of human bocavirus, human coronavirus-NL63, human metapneumovirus, human polyomavirus KI and WU in respiratory tract infections in Kuwait

Epidemiological and clinical study of viral respiratory tract infections in children from Italy

Human bocavirus in French children

Detection of novel respiratory viruses from influenza-like illness in the Philippines

Seroepidemiology of human bocavirus in

Fatal type 7 adenovirus associated with human bocavirus infection in a healthy child

High rate of human bocavirus and adenovirus coinfection in hospitalized Israeli children

Seroepidemiology of human bocavirus infection in Jamaica

Pediatric hospitalization of acute respiratory tract infections with Human Bocavirus in Hong Kong

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Cytokines and pulmonary fibrosis

The role of the Th2 CC chemokine ligand CCL17 in pulmonary fibrosis

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Human bocavirus VP2 upregulates IFN-beta pathway by inhibiting ring finger protein 125-mediated ubiquitination of retinoic acid-inducible gene-I

Human bocavirus NP1 inhibits IFN-beta production by blocking association of IFN regulatory factor 3 with IFNB promoter

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Serodiagnosis of human bocavirus infection

Detection of spliced mRNA from human bocavirus 1 in clinical samples from children with respiratory tract infections