NS1 is a multi-functional protein. NS1 induces a DNA damage response that is essential for virus replication. The central region of NS1 protein exhibits putative helicase activity. The kDa protein is expressed at high levels during B19V infection and localizes more in the cytoplasm than in the nucleus of infected cells. The abundance of the kDa protein in infected cells is at least times greater than NS1 protein St Amand and Astell, ; Chen et al.
The kDa protein is potent inducer of apoptosis during B19V infection and involves caspase Figure 2 Chen et al. Finally, the kDa protein has also been implicated in VP2 production and its distribution Zhi et al. VP1 expression is low Ozawa et al. VP2 has a nuclear localization signal at its C-terminus, therefore both the VP1 and VP2 proteins are found in the nucleus of infected cells Pillet et al.
The capsid first interacts with P antigen Figure 2 Brown et al. VP1u region from to amino acids exhibits phospholipase A2 activity Dorsch et al. The non-structural proteins need to be further investigated for their functional characterization. B19V replication takes place in the nucleus of the infected cells. B19V genome RF contains a bp nt — long minimum origin of replication Ori at each ends Guan et al.
Although the origins function independently, but both origins are required for the efficient DNA replication of the virus Ganaie et al.
After NS1 nicking, DNA replication continues, and presumably follows rolling hairpin model of replication Figure 2 , as suggested for other parvoviruses Tattersall et al. Broadly, B19V replication is regulated by the following factors:.
In response to low oxygen tension, human kidney interstitial fibroblasts secrete EPO, a glycoprotein cytokine that promotes the differentiation and development of erythroid progenitors that results in the production of mature RBCs Testa, The exclusive tropism of B19V for erythroid progenitor cells partly depends on the expression of receptor and co-receptors on the cell surface and partly on the essential host cellular factors for efficient virus replication.
Erythroid lineage cells depend on EPO for survival Grebien et al. B19V-semi permissive cell lines e. The viremia in B19V infected patients goes up to 10 13 genomic copies per ml of plasma Wong and Brown, ; Takano and Yamada, , which indicates the requirement of other factors in determining the production of virions. Oxygen tension is low in bone marrow Rogers et al. Increase in the productive B19V infection under hypoxic conditions wasn't due to increase in the B19V entry or intracellular trafficking of the virus.
The efficient replication of M20 infectious clone and the subsequent production of infectious virions holds promise to study B19V replication and the underlying mechanism s of replication.
Also, mutagenesis of B19V molecular clone M20 could help to understand the role of individual viral proteins and the specific protein domains in virus replication. The sequestration of cyclin B1 to the cytoplasm in B19V-infected cells indicates that B19V somehow prevents its import to nucleus, thus results into cell cycle arrest at G2 phase Morita et al.
Like other autonomous parvoviruses, B19V infection also induces arrest at S phase Luo et al. It is likely that like other parvoviruses Parris and Bates, ; Oleksiewicz and Alexandersen, ; Deleu et al.
In addition, replication protein A RPA32 also colocalizes with viral replicating machinery. Although phosphorylated RPA32 forms also show colocalization, phosphorylation itself seems dispensable for virus replication Zou et al. It was found that replicating, infectious clone-M20, but not a replication deficient M20 mutant, led to the induction of DDR Lou et al. In conclusion, Epo signaling and the virus induced- DDR and late S-phase arrest are essential for the efficient virus replication.
These findings have revealed the new mechanistic insights into B19V replication and also helped in the identification of novel targets for inhibiting B19V at the replication level. However, It remains to be seen that how virus infection-induced DDR promotes the efficient B19V replication in the erythroid cells? B19V infection induces cell cycle arrest at G2 phase Morita et al.
Upon further analyses of the cell cycle during the virus infection, it was found that the arrest at G2 phase has 4N DNA content but also incorporates BrdU, a thymidine analog, suggesting that the infected cells are in late S phase Luo et al. During early infection, the cells are precisely at late S phase, however, at the late phase of infection most infected cells are found in G2 phase Luo et al.
There are many players responsible for inducing cell cycle arrest during B19V infection. Recently, we explored the underlying mechanism of the NS1 induced cell cycle arrest in great detail Xu et al. Phosphorylated CDC25C at S reduces its phosphatase activity and renders it complexed with protein in the cytoplasm Peng et al. It appears that NS1 or DNA replication mediated activation of ATR transduce signaling through different downstream pathways and results in cells arrested at different phases of cell cycle.
The last factor implicated in B19V infection induced cell cycle arrest is the viral genome itself. This promoter sequence is a CpG oligodoxynucleotide analog that is a ligand of toll-like receptor 9 TLR9. The B19V encoded kDa protein is also implicated in causing cell death through apoptosis, which involves caspase Chen et al.
It was found that kDa is a more potent inducer of apoptosis than NS1 Chen et al. Virus infection is seen in non-erythroid cells as well. The virus uses an alternative entry route by complexing with antibody and entering through complement factor C1q and C1q receptor mediated endocytosis von Kietzell et al. There is no clear evidence that B19V replicates or produces virions in any non-erythroid cell lineage, hence the infection is considered largely non-productive.
B19V predominantly infects endothelial cells of various tissues e. Other cell lines infected include U cells Munakata et al. Even after the infection is resolved, the viral DNA can be found in various tissues like spleen, liver, tonsils, testes and brain Kerr, ; Adamson-Small et al. Upon infection, the infected tissue evokes host-cellular response against the virus which culminates in a myriad of pathologies.
B19V infection has been linked to several inflammatory diseases like cardiomyopathy Simpson et al. B19V infection or the expression of viral proteins can modulate the immune response.
Particularly, in synoviocytes, VP1u phospholipase A2 activity is implicated in the production of inflammatory response Lu et al.
NS1 induces apoptosis in hepatocytes through the activation of caspse-3 and caspase-9 Poole et al. In conclusion, the B19V productive infection causes cell death of the erythroid progenitors and the non-productive infection of non-erythroid tissues evokes inflammatory responses that leads to various pathologies.
However, with the exception of the placental endothelium Pasquinelli et al. However, such persistent infection is at sub-immunogenic levels, as viral load is kept under control by our immune system Anderson et al. During times when patients are under immunosuppression or during infection with other pathogens, the viral load increases, causing extensive cell death of erythroid progenitor cells and leads to various inflammatory diseases as described above Heegaard and Brown, ; Qiu et al.
The new advancements in the field of B19V viral replication have identified various critical steps during the process of virus replication. Recently, an in-vitro nicking assay for NS1 was developed Sanchez et al. Furthermore, since the VP1u region is essential for viral entry and therefore, the peptide analogs of VP1u Leisi et al. However the levels used in patients are too low to inhibit B19V. Therefore, derivatives of pimozide could be explored as potential drugs for B19V infection and for B19 related pathologies and included in prophylactic antivirals for transplant recipients.
However, the development of new antivirals against B19V infection needs an animal model to validate any new treatment. All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Adamson-Small, L. Persistent parvovirus B19 infection in non-erythroid tissues: possible role in the inflammatory and disease process.
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Human parvovirus B19 nonstructural NS1 protein induces apoptosis in erythroid lineage cells. Momoeda, M. However, necrosis, has also been reported during infection of the minute virus of mice, parvovirus H-1 and bovine parvovirus. Contact Us Home. The virion penetrates into the cytoplasm via permeabilization of host endosomal membrane.
Microtubular transport of the virion toward the nucleus. The viral ssDNA genome penetrates into the nucleus. Replication occurs through rolling-hairpin mechanism, with NS1 endonuclease binding covalently to the 5' genomic end. Individual ssDNA genomes are excised from replication concatemers by a process called junction resolution. Host-virus interaction Apoptosis modulation Parvoviruses infection induces host cell death, which is often directly associated with disease outcomes.
Polyarthropathy syndromes in adults.
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