Principal Investigator: Prof. Arnab Pain

Poster Presenter: Amit Kumar Subudhi



A Plasmodium-specific AP2-P regulates multiple pathogenicity factors with dual expression peaks during the IDC




Malaria pathogenicity results from the parasite’s ability to invade, multiply within and then egress from the host red blood cell (RBC). Infected RBCs are remodelled, expressing antigenic variant proteins (such as PfEMP1, coded by the var gene family) for immune evasion and survival. These processes require the concerted actions of many proteins, but the molecular regulation is poorly understood. We have characterized an essential Plasmodium-specific Apicomplexan AP2 (ApiAP2) transcription factor in Plasmodium falciparum (PfAP2-P; Pathogenesis) during the intraerythrocytic developmental cycle (IDC). An inducible gene knockout approach showed that PfAP2-P is essential for development during the trophozoite stage, and critical for var gene regulation, merozoite development and parasite egress. ChIP-seq experiments were performed at 16 hours post-invasion (h.p.i.) and 40 h.p.i. matching the two peaks of PfAP2-P expression, demonstrating the binding of PfAP2-P to the promoters of genes controlling antigenic variation, host cell remodelling and trophozoite development at 16 h.p.i. and antigenic variation and pathogenicity at 40 h.p.i. Using single-cell RNA-seq and fluorescence-activated cell sorting, we show the de-repression of var gene expression in Δpfap2-p parasites that express multiple PfEMP1 proteins on the surface of infected RBCs. In addition, the Δpfap2-p parasites overexpress several early gametocyte marker genes at both 16 and 40 h.p.i., indicating a putative regulatory role in the sexual stage conversion. Using the Chromosome Conformation Capture (Hi-C) experiment, we demonstrate that deletion of PfAP2-P results in a significant reduction of both intra-chromosomal and inter-chromosomal interactions in heterochromatin clusters. We conclude that PfAP2-P is a vital upstream transcriptional regulator controlling essential pathogenic processes in two distinct developmental stages during the IDC that include parasite growth, egress and invasion, chromatin structure and var gene expression.