The DNA-binding protein PfAP2-V regulates erythrocyte invasion and pathogenesis of the human malaria parasite Plasmodium falciparum

The pathogenesis of Plasmodium falciparum malaria involves coordinated molecular events, including host cell invasion, intraerythrocytic replication cycles, and antigenic variation, which are critically dependent on the stage-specific regulation of parasite proteins. Despite their biological significance, the molecular governance of these pathogenic mechanisms remains inadequately characterized. Our investigation reveals that the expression dynamics of an ApiAP2 family transcription factor, PfAP2-V, exhibits strong temporal coordination with the transcriptional activation of virulence-associated genes during the blood-stage development of P. falciparum parasites. These genes encompass those coding for merozoite surface antigens and the inner membrane complex families and the var gene clusters encoding P. falciparum erythrocyte membrane protein 1 (PfEMP1) cytoadherence proteins. Conditional knockdown of pfap2-v expression significantly decreased parasite intraerythrocytic proliferation, resulted in structural abnormalities in infected erythrocyte surface topology, and markedly reduced the cytoadhesion capacity of infected erythrocytes to human endothelial receptors, such as CD36, ICAM-1 and PECAM-1/CD31. Mechanistic analyses revealed that PfAP2-V directly associates with specific chromosomal regions, where it is involved in chromatin interactions and facilitates transcriptional activation. These findings establish PfAP2-V as a master transcriptional regulator that governs both parasite proliferation and the expression of the virulence factors critical for P. falciparum malaria pathogenesis.