During malaria infection, Plasmodium spp. parasites cyclically invade red blood cells and can follow two different developmental pathways. They can either replicate asexually to sustain the infection, or differentiate into gametocytes, the sexual stage that can be taken up by mosquitoes, ultimately leading to disease transmission. Despite its importance for malaria control, the process of gametocytogenesis remains poorly understood, partially due to the difficulty of generating high numbers of sexually committed parasites in laboratory conditions1. Recently, an apicomplexa-specific transcription factor (AP2-G) was identified as necessary for gametocyte production in multiple Plasmodium species2,3, and suggested to be an epigenetically regulated master switch that initiates gametocytogenesis4,5. Here we show that in a rodent malaria parasite, Plasmodium berghei, conditional overexpression of AP2-G can be used to synchronously convert the great majority of the population into fertile gametocytes. This discovery allowed us to redefine the time frame of sexual commitment, identify a number of putative AP2-G targets and chart the sequence of transcriptional changes through gametocyte development, including the observation that gender-specific transcription occurred within 6 h of induction. These data provide entry points for further detailed characterization of the key process required for malaria transmission.
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We thank R. Menard and D. Bargieri for the diCre test plasmid used in this study, and M. Sanders and the WTSI sequencing service for assistance with RNA-seq sample processing. K.K.M. is supported by the Wellcome Trust and the Royal Society (ref. 202600/Z/16/Z). R.S.K. is supported by BBSRC (ref. BB/J013854/1). A.P.W. is supported by the Wellcome Trust (refs 083811 and 107046). O.B. is supported by the Wellcome Trust Sanger Institute (ref. WT098051).
The authors declare no competing interests.
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Supplementary Materials, Supplementary Figures 1–9, legends for Supplementary Tables 1–3 and original blots.
List of oligonucleotide primers used in the study.
Differential gene expression analysis between PBGAMiR+ and PBGAMiR populations at various time points post induction.
Gene ontology terms enriched in genes differentially expressed at different time points post induction.
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Kent, R.S., Modrzynska, K.K., Cameron, R. et al. Inducible developmental reprogramming redefines commitment to sexual development in the malaria parasite Plasmodium berghei. Nat Microbiol 3, 1206–1213 (2018). https://doi.org/10.1038/s41564-018-0223-6
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