The host cell transcription factor hypoxia-inducible factor 1 is required for Toxoplasma gondii growth and survival at physiological oxygen levels

Toxoplasma gondii is an obligate intracellular protozoan pathogen. We previously found that genes mediating cellular responses to hypoxia were upregulated in Toxoplasma -infected cells but not in cells infected with another intracellular pathogen, Trypanosoma cruzi. The inducible expression of these genes is controlled by the hypoxia-inducible factor 1 (HIF1) transcription factor, which is the master regulator of cells exposed to low oxygen. Because this response may be important for parasites to grow at physiological oxygen levels, we tested the hypothesis that HIF1 is important for Toxoplasma growth. Here, we demonstrate that Toxoplasma infection rapidly increased the abundance of the HIF1 alpha subunit and activated HIF1 reporter gene expression. In addition, we found that Toxoplasma growth and survival was severely reduced in HIF1 alpha knockout cells at 3% oxygen. While HIF1 alpha was not required for parasite invasion, we determined that HIF1 was required for parasite cell division and organelle maintenance at 3% oxygen. These data indicate that Toxoplasma activates HIF1 and requires HIF1 for growth and survival at physiologically relevant oxygen levels.