Introduction
Parvovirus B19 (B19V) is a human-pathogenic virus known for its highly specific tropism towards human erythroid progenitor cells (EPCs). This small, non-enveloped virus measures about 23-26 nm in diameter and possesses a linear single-stranded DNA genome approximately 5.6 kb in length, flanked by two identical terminal hairpin structures. Initially identified during hepatitis B virus screenings, B19V emerged from sample number 19 in panel B. B19V infection in humans can lead to a variety of diseases, ranging from fifth disease in children to more severe conditions like transient aplastic crisis, non-immune hydrops fetalis during pregnancy, persistent anemia in immunocompromised patients, and several inflammatory conditions.
Fig. 1 Schematic diagram of B19V genome. (Zakrzewska K., et al. 2023)
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Viral Tropism and Cellular Entry
B19V exhibits a unique tropism for human erythroid progenitor cells, particularly those from the burst-forming unit-erythroid (BFU-E) to colony-forming unit-erythroid (CFU-E) stages. The virus can infect ex vivo expanded erythroid progenitor cells from bone marrow, peripheral blood, and the fetal liver, but its replication is typically restricted to cells expressing the P antigen (globoside). Despite this specificity, B19V can also interact with endothelial cells and other cell types, though these interactions are generally non-productive.
The primary receptor for B19V is globoside, but its interaction with other co-receptors like Ku80 and integrin α5β1 plays a crucial role in viral entry. B19V utilizes an endocytic pathway for internalization, avoiding lysosomal degradation to reach the nucleus where it replicates and transcribes. VP1u, a unique domain of the VP1 capsid protein, is critical for viral entry, interacting with cellular factors to facilitate the virus's internalization.
Viral Gene Expression and Splicing
Once inside the nucleus, the B19V genome is converted into a double-stranded replicative form (dsRF) that serves as a template for replication and transcription. The virus produces a single precursor mRNA (pre-mRNA) from the P6 promoter, which undergoes extensive splicing to generate multiple mature mRNA transcripts. These transcripts encode various viral proteins including two structural proteins (VP1 and VP2) and three non-structural proteins (NS1, 7.5-kDa, and 11-kDa).
The pre-mRNA contains several splice donor and acceptor sites, along with proximal and distal polyadenylation sites. Alternative splicing and polyadenylation result in different protein products at various stages of infection. The 7.5-kDa protein and NS1 protein are produced early in the infection, while VP1 and VP2 are expressed later. The balance between these proteins is regulated by the availability of splicing factors and polyadenylation sites.
Regulation of B19V Gene Expression
B19V gene expression is tightly regulated by several factors, including erythropoietin (EPO) signaling, hypoxia, and late S-phase arrest. EPO signaling is crucial for B19V replication, as it enhances the expression of EPO receptors and activates the JAK2-STAT5 pathway, which in turn promotes viral gene expression. Hypoxia, or low oxygen conditions, also influences B19V replication by upregulating STAT5 and modulating MEK/ERK signaling pathways. These conditions create a favorable environment for viral replication.
Late S-phase arrest induced by B19V is another critical factor for efficient replication. The NS1 protein plays a key role in this process by interacting with cell cycle regulators and inducing G2/M phase arrest. This arrest allows for the accumulation of cellular factors necessary for viral DNA replication and packaging.
Viral Proteins and Their Functions
Non-Structural Proteins
The NS1 protein is multifunctional and plays several roles in the B19V life cycle. It is essential for viral DNA replication, transcription activation, and inducing apoptosis. NS1 interacts with the Mre11-Rad50-Nbs1 (MRN) complex involved in DNA damage response and modulates cell cycle progression by inhibiting cyclin-dependent kinases (CDKs). Additionally, NS1 induces the production of reactive oxygen species (ROS), which contributes to cellular apoptosis.
The 11-kDa protein, produced from spliced mRNA with an alternative polyadenylation site, enhances viral replication and affects cellular apoptosis. It is associated with the production of VP2 and plays a role in modifying the cell cycle, although its exact function is still under investigation.
The 7.5-kDa protein is expressed from spliced mRNA that uses the proximal polyadenylation site. Its precise role in B19V replication and pathogenesis remains less well understood, and further research is needed to elucidate its functions.
Structural Proteins
VP1 and VP2 are the major structural proteins of the B19V capsid. VP1, the larger of the two, contains VP1u, a domain crucial for receptor binding and viral entry. VP2, while more abundant, stabilizes the capsid and assists in DNA encapsidation. The interaction between VP1 and VP2 is essential for the formation of a stable and functional viral capsid.
Therapeutic Insights and Future Directions
Despite the progress in understanding B19V biology, there are still challenges in developing effective therapies for B19V infection. The virus's ability to induce various diseases, including fifth disease, transient aplastic crisis, and non-immune hydrops fetalis, highlights the need for targeted therapeutic approaches.
Recent research has focused on identifying potential therapeutic targets and strategies. For example, targeting the NS1 protein or its interactions with cellular factors may provide a means to inhibit viral replication and alleviate disease symptoms. Additionally, exploring the roles of host factors such as STAT5 and RBM38 in B19V replication and mRNA processing could lead to novel therapeutic approaches.
Future research should also focus on understanding the mechanisms of viral tropism, entry, and replication in different cell types. This knowledge will aid in the development of targeted therapies and preventive measures for B19V-related diseases. Furthermore, investigating the interactions between B19V and the host immune system may provide insights into immune-mediated responses and potential vaccine candidates.
Conclusion
Parvovirus B19 presents a complex challenge due to its ability to cause various diseases and its specific tropism for erythroid progenitor cells. Recent advances have shed light on its tropism, replication mechanisms, and gene expression regulation. Key factors such as EPO signaling, hypoxia, and late S-phase arrest are crucial for B19V replication. The roles of NS1 and other viral proteins in regulating cell cycle progression and viral replication are central to understanding B19V pathogenesis. Future research should continue to explore these mechanisms and seek new therapeutic strategies to manage B19V-related diseases effectively. As our understanding deepens, targeted treatments and preventive measures may become available to address the diverse clinical manifestations of B19V infection.
References
- Zakrzewska K., et al. Parvovirus B19: Insights and implication for pathogenesis, prevention and therapy. Aspects of Molecular Medicine. 2023, 1: 100007.
- Ganaie S. S., Qiu J. Recent advances in replication and infection of human parvovirus B19. Frontiers in Cellular and Infection Microbiology. 2018, 8: 166.
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