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% O2 (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.
Highlights
Human parvovirus B19 (B19V) is the only parvovirus so far confirmed to be pathogenic to humans [1]
Human parvovirus B19 (B19V) is the etiological agent of fifth disease seen in children, aplastic crisis in sickle cell disease patients, chronic anemia in immunocompromised patients, and hydrops fetalis in pregnant women
For the first time, a long-term B19V infection of ex vivo expanded erythroid progenitor cells at hypoxia
Summary
Human parvovirus B19 (B19V) is the only parvovirus so far confirmed to be pathogenic to humans [1]. Infection by this virus is the cause of the highly contagious ‘‘fifth disease’’ in children. It can result in serious, and occasionally fatal, hematologic diseases in susceptible patients. Acute B19V infection can cause transient aplastic crisis in patients with high levels of red blood cell destruction and erythrocyte turnover (e.g., sickle-cell disease patients). Aplastic crisis in the fetus and hydrops fetalis can occur as a result of infection-induced anemia in pregnant women [3]
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