Isolation and functional characterization of two distinct sexual-stage-specific promoters of the human malaria parasite Plasmodium falciparum

Transmission of malaria depends on the successful development of the sexual stages of the parasite within the midgut of the mosquito vector. The diffe rentiation process leading to the production of the sexual stages is deline ated by several developmental switches. Arresting the progression through t his sexual differentiation pathway would effectively block the spread of th e disease. The successful development of such transmission-blocking agents is hampered by the lack of a detailed understanding of the program of gene expression that governs sexual differentiation of the parasite. Here we des cribe the isolation and functional characterization of the Plasmodium falci parum pfs16 and pfs25 promoters, whose activation marks the developmental s witches executed during the sexual differentiation process. We have studied the differential activation of the pfs16 and pfs25 promoters during intrae rythrocytic development by transfection of P. falciparum and during gametog enesis and early sporogonic development by transfection of the related mala rial parasite P. gallinaceum. Our data indicate that the promoter of the pf s16 gene is activated at the onset of gametocytogenesis, while the activity of the pfs25 promoter is induced following the transition to the mosquito vector. Both promoters have unusual DNA compositions and are extremely A/T rich. We have identified the regions in the pfs16 and pfs25 promoters that are essential for high transcriptional activity. Furthermore, we have ident ified a DNA-binding protein, termed PAF-1, which activates pfs25 transcript ion in the mosquito midgut. The data presented here shed the first light on the details of processes of gene regulation in the important human pathoge n P. falciparum.