The Plasmodium falciparum ApiAP2 transcription factor PfAP2-V controls parasite proliferation and virulence in intra-erythrocytic developmental cycle

Malaria pathogenesis, encompassing parasite invasion, egress, and antigenic variation, relies on the coordinated activity of numerous proteins, yet their molecular regulatory mechanisms remain poorly understood. Here, we define the role of PfAP2-V, a critical AP2 transcription factor in Plasmodium falciparum, during intra-erythrocytic developmental cycle. PfAP2-V displayed two distinct peaks of expression and was critical for parasite proliferation, invasion, and the regulation of virulence-associated genes. Inducible knockdown of PfAP2-V reduced parasitemia by blocking trophozoite development, which was associated with downregulated phosphorylation of virulence-associated proteins. Furthermore, PfAP2-V knockdown reduced PfEMP1 expression, impairing the adhesion of infected red blood cells to endothelial receptors. Genome-wide chromosome conformation capture and chromatin immunoprecipitation sequencing analyses revealed that PfAP2-V knockdown altered chromatin interactions and accessibility, disrupting the regulation of antigenic variant genes. These findings establish PfAP2-V as a key transcriptional regulator at distinct stages of the intra-erythrocytic cycle. The intrinsic mechanism of PfAP2-V regulation in P. falciparum was explored by single-cell RNA sequencing (scRNA-seq) analysis. A single-cell transcriptome profiles of PfAP2-V knockdown strains of P. falciparum before and after 5 mM treatment were constructed.