Human parvovirus B19 (B19V) infection causes hydrops fetalis in pregnant women during the second- trimester. It also causes severe hematological diseases, including transient aplastic crisis in patients with a high turn-over rate f red blood cells;and chronic anemia in immunodeficient and immunocompromised patients which, in some cases, can be fatal. At present, no specific antiviral drugs or vaccines (that prevent B19V infection in high-risk groups) are available. B19V replication is highly restricted to human erythroid progenitor cells (EPCs) in the bone marrow and fetal liver. B19V infection-mediated hydrops fetalis and hematological disorders mainly result from the direct killing of the EPCs in which B19V replicates. Among DNA viruses, B19V has a unique feature in the processing of its precursor mRNA (pre-mRNA) in that all the viral mRNAs are alternatively processed from a single pre-mRNA. Alternative splicing of the B19V pre-mRNA, which is controlled by multiple splicing enhancers, plays a key role in regulating alternative polyadenylation of B19V mRNAs, and generates abundant small viral mRNAs for encoding two small non- structural viral proteins, i.e. 7.5-kDa and 11-kDa. The 11-kDa protein interacts with Grb2, a protein that links the signals mediated by the erythropoietin receptor to the Ras/MEK/ERK pathway in EPCs, and plays an important role in viral DNA replication. Importantly, B19V infection induces a DNA damage response (DDR). Activation of ATR and DNA-PKcs facilitates viral DNA replication. B19V does not use the host replication machinery to replicate its ssDNA genome;rather, it appears to induce a DDR and subsequently co-opts the host DNA repair mechanism to facilitate its own replication. Furthermore, B19V replication in EPCs is markedly increased under hypoxic conditions and is mediated via the down-regulation of MEK/ERK signaling. Over the past few years, we have established two experimental cell systems that remove two critical barriers to the study of B19V replication: an efficient system of productive B19V infection involving the ex vivo- expansion of EPCs under hypoxic conditions (which mimic the microenvironment of EPCs in human bone marrow and fetal liver), and a reverse genetics approach that involves transfection of the B19V dsDNA-form genome into UT7/Epo-S1 cell line cells cultured under hypoxic conditions. Using these two systems, as well as a newly-established in vitro assay to measure viral DNA replication, we will: i) determine the mechanisms underlying the alternative processing of B19V pre-mRNA;ii) elucidate the mechanisms by which the 11-kDa protein subverts MEK/ERK signaling to promote B19V replication;and iii) determine the mechanisms underlying DDR-facilitated B19V DNA replication. Our long-term goal is to identify the key molecular mechanisms underlying the alterative processing of the single promoter-transcribed parvoviral pre-mRNA, as well as parvovirus DNA replication, in a physiologically- relevant setting, i.e., EPCs ex vivo-expanded under hypoxic conditions for B19V in this application.

Public Health Relevance

Human parvovirus B19 (B19V) causes severe anemia and hydrops fetalis in humans. B19V infection- caused anemia is the direct outcome of cell death of human erythroid progenitor cells, in which B19V replicates. Thus, our studies on replication of B19V in ex vivo-expanded primary human erythroid progenitor cells will answer critical questions in the pathogenesis of B19V infection, and have the potential to identify host factors and pathways that can be targeted for development of antiviral drugs to treat infected patients.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Virology - B Study Section (VIRB)
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Park, Eun-Chung
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University of Kansas
Schools of Medicine
Kansas City
United States
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