A transcriptional cascade as therapeutic target for malaria controls. Plasmodium falciparum

Malaria annually causes more than 500,000 deaths globally and continues to evade eradication owing to drug resistance and inefficient prevention. Variation in the usage of multiple invasion pathways is the key pathogenic basis of the disease’s success. Despite some parasite proteins have been identified in P. falciparum infection including merozoite egress and invasion to Red Blood Cells (RBCs), the key factors controlling these processes remain elusive. Here we report a transcriptional cascade that regulates the pathogenesis of P. falciparum infection. A histone H3 lysine 4 (H3K4) demethylase PfLSD2 represses the expression of an essential apetela2-type transcriptional factor gene PfAP2P in the late blood stage parasites via erasing H3K4 dimethylation at the promoter region, and subsequently regulates parasite invasion and egress as well as sexual commitment of P. falciparum. Notably, knockdown of PfAP2P reduced the expression of infection genes and rescued the phenotypes in the PfLSD2 knockout (PfLSD2Δ) parasites. Genome-wide transcriptome analyses indicated that the majority of invasion and egress genes were co-regulated by the PfLSD2/PfAP2P cascade. With high occupancy of PfAP2P at specific motifs in the promoter regions, most of infection genes were transcribed by PfAP2P and further promoted by PfAP2P overexpression. The expression level of PfAP2P showed significantly positive correlation with the asexual reproduction rate of the freshly-adapted field isolates of P. falciparum, whereas PfLSD2 did reversely. More importantly, the specific PfAP2P-binding DNA oligo was successfully applied to kill the asexual P. falciparum by competitively blocking the function of PfAP2P. These results identify PfLSD2 and PfAP2P as a transcriptional cascade that sequentially controls P. falciparum infection and sexual commitment, providing new strategies for malaria controls.