Mechanisms of Sexual DEtermination in Wild mAlaria parasiteS – SiDEWAyS

Malaria is caused by parasites of the genus Plasmodium. Whilst the disease is caused by asexual parasites, only sexual forms are capable of transmitting the infection to mosquitoes. Sexual forms arise from a small subset of blood-stage parasites which divert from the cycle of asexual replication and embark on a sexual developmental trajectory. The bifurcation leading to a sexual fate is dependent on the master regulator of sex, the transcription factor AP2-G. In the absence of sex chromosomes or conserved sex-determining mechanisms, events that lead to determination into either a male or a female are completely unknown. In this project, we will use single-cell technology and reverse genetics to identify and characterise genes involved in the sex-determining pathway of the human malaria parasite P. falciparum. Sex-determination is influenced by external cues, which are best measured in natural environments; we will therefore also investigate the sex-determining pathway directly in naturally-infected carriers in Mali using single-cell RNAseq. With this powerful approach, we can establish the stage, genotype, and transcriptome of every parasite we examine and can compare any two parasite cells, including cells within and between hosts and stages. Not only can this establish the natural variation in sex-determination expression patterns, but also identify parasite and host factors that play a role in the environmental determination of sex. In addition, we will investigate the sequence diversity in sex-determining genes in P. falciparum to understand how the parasite might maximise its reproductive fitness in natural populations. Targeting sex-determination to sterilise population of parasites in the host could be used as a strategy to interrupt transmission to mosquitoes. The findings of this project will, therefore, provide new biological insights into sex-determination in malaria-parasites and assist in the identification of new drug targets.