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.