Dissecting the role of a novel ApiAP2 transcription factor during sexual development of Plasmodium falciparum

Malaria infection leads to severe cardiovascular complications due to the adherence of parasite-infected red blood cells to the vascular epithelium. This is particularly notable in the heart and brain resulting in lethal outcomes. Despite its neglect, malaria remains a critical global health threat, with Plasmodium falciparum being the deadliest species responsible for over 600,000 annually deaths, mainly in young children. Parasite transmission by mosquitoes relies on the development of mature sexual parasites, or gametocytes, which are taken up during a blood meal. Sexual development begins with commitment from asexually replicating parasites and a subsequent 10-12-day maturation process in human blood resulting in male and female gametocytes. Although recent progress has been made toward understanding the regulation of male gametocyte sex determination, the mechanisms underlying female gametocyte differentiation remain largely unknown, presenting a critical gap in our knowledge. Preliminary data indicate that PfFD3 is crucial for gametocytogenesis, as its knockdown induces developmental arrest at stages III/IV, prior to male and female differentiation. To uncover the molecular mechanisms through which PfFD3 influences sexual development, Isadora Prata will map the targets of PfFD3 genome-wide by ChIP-seq at various timepoints and assess the specific regulatory cascades triggered by this TF. Furthermore, Prata will use a genetically engineered line to induce PfFD3 knockdown at various stages of development, allowing for a systematic characterization of the resulting developmental arrest. Additionally, this project will use single-cell RNA sequencing (scRNA-seq) following PfFD3 disruption to capture the dynamic changes in lineage-specific transcriptional events throughout parasite sexual development. Complementary bulk RNA-seq will comprehensively capture transcriptomics changes associated with PfFD3 activity to identify putative target genes and define key downstream regulatory networks. The outcomes of this study are expected to reveal novel targets for transmission-blocking interventions, contributing to the development of future next-generation antimalarial therapies.

Basic Science

Jan 2025 — Dec 2026

$156,640

United States