Plasmodium HDAC1 and the liver stage growth

Compared to their mammalian hosts, apicomplexan parasite genomes including Plasmodium lack RNA interference machinery and possess limited transcription factors to regulate gene expression. In return, gene expression and phenotype control through epigenetic regulatory enzymes that post-transcriptionally modify histones is considerable. There is accumulating evidence that a Plasmodium epigenetic enzyme, histone deacetylase 1 (HDAC1), is essential for parasite life cycle progression and is a promising therapy target. We studied the contribution of Plasmodium histone deacetylase 1 to parasite liver stage growth through specific inhibition of its deacetylase activity by an HDAC inhibitor molecule (hdaci). Unlike Toxoplasma gondii and Theileria annulata, where it was previously shown that exposure of highly proliferative life cycle stages (tachyzoites and schizonts, respectively) to hdaci provoked a developmental switch to the next life cycle stage (bradyzoites and merozoites, respectively); in Plasmodium hdaci blocked development of intrahepatic schizonts of all P. berghei, P. falciparum, P. cynomolgi and P. vivax. Furthermore, RNA-sequencing of FACS-sorted GFP expressing Plasmodium berghei from ex vivo-infected primary hepatocyte cultures treated, or not with hdaci demonstrated that growth arrest was due to strong induction of genes typically expressed at other life cycle stages such as in sporozoites (e.g. PbAP2-SP and PbUIS4) and gametocytes (e.g. PbHMGB2). In addition, merozoite surface protein (PbMSP1), whose transcripts significantly augment during liver stage development, was downregulated by hdaci treatment. Our results confirm a previous observation that HDAC1 inhibition blocked growth and differentiation of P. berghei parasites and underline that HDAC1 is a potent transcriptional regulator and therapeutic target of liver stage parasites from multiple Plasmodium species.