title: Productive parvovirus B19 infection of primary human erythroid progenitor cells at hypoxia is regulated by STAT5A and MEK signaling but not HIFα.
abstract: Human parvovirus B19 (B19V) causes a variety of human diseases. Disease outcomes of bone marrow failure in patients with high turnover of red blood cells and immunocompromised conditions, and fetal hydrops in pregnant women are resulted from the targeting and destruction of specifically erythroid progenitors of the human bone marrow by B19V. Although the ex vivo expanded erythroid progenitor cells recently used for studies of B19V infection are highly permissive, they produce progeny viruses inefficiently. In the current study, we aimed to identify the mechanism that underlies productive B19V infection of erythroid progenitor cells cultured in a physiologically relevant environment. Here, we demonstrate an effective reverse genetic system of B19V, and that B19V infection of ex vivo expanded erythroid progenitor cells at 1% O(2) (hypoxia) produces progeny viruses continuously and efficiently at a level of approximately 10 times higher than that seen in the context of normoxia. With regard to mechanism, we show that hypoxia promotes replication of the B19V genome within the nucleus, and that this is independent of the canonical PHD/HIFα pathway, but dependent on STAT5A and MEK/ERK signaling. We further show that simultaneous upregulation of STAT5A signaling and down-regulation of MEK/ERK signaling boosts the level of B19V infection in erythroid progenitor cells under normoxia to that in cells under hypoxia. We conclude that B19V infection of ex vivo expanded erythroid progenitor cells at hypoxia closely mimics native infection of erythroid progenitors in human bone marrow, maintains erythroid progenitors at a stage conducive to efficient production of progeny viruses, and is regulated by the STAT5A and MEK/ERK pathways.
authors.affiliation: Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, Kansas City, Kansas, United States of America.
authors.forename: Aaron Yun
authors.initials: AY
authors.lastname: Chen
authors.forename: Steve
authors.initials: S
authors.lastname: Kleiboeker
authors.forename: Jianming
authors.initials: J
authors.lastname: Qiu
mesh_terms: D018955:CD36 Antigens / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D004261:DNA Replication; D016731:Erythema Infectiosum / Q000150:complications / Q000378:metabolism / Q000821:virology*; D015672:Erythroid Precursor Cells / Q000378:metabolism / Q000473:pathology / Q000502:physiology / Q000821:virology*; D006801:Humans; D000860:Hypoxia / Q000150:complications / Q000473:pathology* / Q000821:virology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism / Q000502:physiology*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000502:physiology; D008954:Models, Biological; D016732:Parvovirus B19, Human / Q000502:physiology*; D050799:STAT5 Transcription Factor / Q000378:metabolism / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000378:metabolism / Q000502:physiology*; D014779:Virus Replication / Q000235:genetics / Q000502:physiology
chemical_list: D018955:CD36 Antigens; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; D025521:Tumor Suppressor Proteins; D020930:MAP Kinase Kinase Kinases