Serologically verified human bocavirus pneumonia in children

Don, Massimiliano; Söderlund‐Venermo, Maria; Valent, Francesca; Lahtinen, Aira; Hedman, Lea; Canciani, Mario; Hedman, Klaus; Korppi, Matti

doi:10.1002/ppul.21151

Cited by 86 publications

(76 citation statements)

References 32 publications

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“…Many studies have been published investigating the role of the virus in respiratory tract illness (6). Some raise the possibility that HBoV is associated with severe respiratory disease (7,8). HBoV is frequently found in hospitalized children under 2 years of age with bronchiolitis, asthma exacerbation, and wheezing (1,11,12).…”

Section: Case Reportmentioning

confidence: 99%

Human Bocavirus as the Cause of a Life-Threatening Infection

et al. 2011

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Section: Case Reportmentioning

confidence: 99%

Human Bocavirus as the Cause of a Life-Threatening Infection

et al. 2011

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“…Other viruses were classified into this genus on the basis of the conservation of viral sequences encoding nonstructural (NS) and structural capsid (Cap) proteins (6)(7)(8)(9). HBoV1 is an emerging human-pathogenic respiratory virus that causes lower respiratory tract infections in young children and is a health concern worldwide (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). In vitro, HBoV1 infects well-differentiated/polarized primary human airway epithelia (HAE) cultured at an air-liquid interface (ALI) (3,22,23).…”

Section: Importancementioning

confidence: 99%

DNA Damage Signaling Is Required for Replication of Human Bocavirus 1 DNA in Dividing HEK293 Cells

Deng

Peng

Zou

et al. 2017

J Virol

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Human bocavirus 1 (HBoV1), an emerging human-pathogenic respiratory virus, is a member of the genus Bocaparvovirus of the Parvoviridae family. In human airway epithelium air-liquid interface (HAE-ALI) cultures, HBoV1 infection initiates a DNA damage response (DDR), activating all three phosphatidylinositol 3-kinaserelated kinases (PI3KKs): ATM, ATR, and DNA-PKcs. In this context, activation of PI3KKs is a requirement for amplification of the HBoV1 genome (X. Deng, Z. Yan, F. Cheng, J. F. Engelhardt, and J. Qiu, PLoS Pathog, 12:e1005399, 2016, https://doi.org/ 10.1371/journal.ppat.1005399), and HBoV1 replicates only in terminally differentiated, nondividing cells. This report builds on the previous discovery that the replication of HBoV1 DNA can also occur in dividing HEK293 cells, demonstrating that such replication is likewise dependent on a DDR. Transfection of HEK293 cells with the duplex DNA genome of HBoV1 induces hallmarks of DDR, including phosphorylation of H2AX and RPA32, as well as activation of all three PI3KKs. The large viral nonstructural protein NS1 is sufficient to induce the DDR and the activation of the three PI3KKs. Pharmacological inhibition or knockdown of any one of the PI3KKs significantly decreases both the replication of HBoV1 DNA and the downstream production of progeny virions. The DDR induced by the HBoV1 NS1 protein does not cause obvious damage to cellular DNA or arrest of the cell cycle. Notably, key DNA replication factors and major DNA repair DNA polymerases (polymerase [Pol ] and polymerase [Pol ]) are recruited to the viral DNA replication centers and facilitate HBoV1 DNA replication. Our study provides the first evidence of the DDR-dependent parvovirus DNA replication that occurs in dividing cells and is independent of cell cycle arrest.IMPORTANCE The parvovirus human bocavirus 1 (HBoV1) is an emerging respiratory virus that causes lower respiratory tract infections in young children worldwide. HEK293 cells are the only dividing cells tested that fully support the replication of the duplex genome of this virus and allow the production of progeny virions. In this study, we demonstrate that HBoV1 induces a DDR that plays significant roles in the replication of the viral DNA and the production of progeny virions in HEK293 cells. We also show that both cellular DNA replication factors and DNA repair DNA polymerases colocalize within centers of viral DNA replication and that Pol and Pol play an important role in HBoV1 DNA replication. Whereas the DDR that leads to the replication of the DNA of other parvoviruses is facilitated by the cell cycle, the DDR triggered by HBoV1 DNA replication or NS1 is not. HBoV1 is the first parvovirus whose NS1 has been shown to be able to activate all three PI3KKs (ATM, ATR, and DNA-PKcs).

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“…Increasing evidence suggests that HBoV1 is an etiological pathogen rather than a bystander in acute respiratory tract infections, especially in children under 5 years of age (3). Acute respiratory infections have been clearly linked to HBoV1 infection as assessed by monodetection, high viral loads (Ͼ10 4 viral genomic copies per ml of respiratory specimen) (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17), the presence of HBoV1-specific IgM, or a Ն4-fold increase in levels of HBoV1-specific IgG antibodies (16,(18)(19)(20).…”

mentioning

confidence: 99%

Parvovirus Expresses a Small Noncoding RNA That Plays an Essential Role in Virus Replication

Wang

Shen

Cheng

et al. 2017

J Virol

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Human bocavirus 1 (HBoV1) belongs to the species Primate bocaparvovirus of the genus Bocaparvovirus of the Parvoviridae family. HBoV1 causes acute respiratory tract infections in young children and has a selective tropism for the apical surface of well-differentiated human airway epithelia (HAE). In this study, we identified an additional HBoV1 gene, bocavirus-transcribed small noncoding RNA (BocaSR), within the 3= noncoding region (nucleotides [nt] 5199 to 5338) of the viral genome of positive sense. BocaSR is transcribed by RNA polymerase III (Pol III) from an intragenic promoter at levels similar to that of the capsid protein-coding mRNA and is essential for replication of the viral DNA in both transfected HEK293 and infected HAE cells. Mechanistically, we showed that BocaSR regulates the expression of HBoV1-encoded nonstructural proteins NS1, NS2, NS3, and NP1 but not NS4. BocaSR is similar to the adenovirus-associated type I (VAI) RNA in terms of both nucleotide sequence and secondary structure but differs from it in that its regulation of viral protein expression is independent of RNA-activated protein kinase (PKR) regulation. Notably, BocaSR accumulates in the viral DNA replication centers within the nucleus and likely plays a direct role in replication of the viral DNA. Our findings reveal BocaSR to be a novel viral noncoding RNA that coordinates the expression of viral proteins and regulates replication of viral DNA within the nucleus. Thus, BocaSR may be a target for antiviral therapies for HBoV and may also have utility in the production of recombinant HBoV vectors.IMPORTANCE Human bocavirus 1 (HBoV1) is pathogenic to humans, causing acute respiratory tract infections in young children. In this study, we identified a novel HBoV1 gene that lies in the 3= noncoding region of the viral positive-sense genome and is transcribed by RNA polymerase III into a noncoding RNA of 140 nt. This bocavirus-transcribed small RNA (BocaSR) diverges from both adenovirus-associated (VA) RNAs and Epstein-Barr virus-encoded small RNAs (EBERs) with respect to RNA sequence, representing a third species of this kind of Pol III-dependent viral noncoding RNA and the first noncoding RNA identified in autonomous parvoviruses. Unlike the VA RNAs, BocaSR localizes to the viral DNA replication centers of the nucleus and is essential for expression of viral nonstructural proteins independent of RNAactivated protein kinase R and replication of HBoV1 genomes. The identification of BocaSR and its role in virus DNA replication reveals potential avenues for developing antiviral therapies.KEYWORDS bocavirus, DNA replication, noncoding RNA, parvovirus H uman bocavirus 1 (HBoV1), which was discovered in 2005 (1), belongs to the species Primate bocaparvovirus 1 in the genus Bocaparvovirus of the Parvoviridae family (2). Increasing evidence suggests that HBoV1 is an etiological pathogen rather than a bystander in acute respiratory tract infections, especially in children under 5

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Serologically verified human bocavirus pneumonia in children

Abstract: The present results show that HBoV is able to induce significant antibody responses and suggest that HBoV may be a fairly common cause of pneumonia in children. Seroconversion to HBoV in most children takes place in early childhood.

Cited by 86 publications

References 32 publications

Human Bocavirus as the Cause of a Life-Threatening Infection

Human Bocavirus as the Cause of a Life-Threatening Infection

DNA Damage Signaling Is Required for Replication of Human Bocavirus 1 DNA in Dividing HEK293 Cells

Parvovirus Expresses a Small Noncoding RNA That Plays an Essential Role in Virus Replication

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