Researchers demonstrate that GEP1 mutations disrupt gametogenesis in Plasmodium falciparum, suggesting its role as a transmission-blocking target.
Transmission of Plasmodium parasites to Anopheles mosquitoes relies on rapid activation of mature gametocytes in the midgut, triggered by a temperature drop and xanthurenic acid. In Plasmodium yoelii , the gametogenesis essential protein 1 (GEP1) was linked to xanthurenic acid (XA)‐dependent gamete activation. We characterized GEP1 in Plasmodium falciparum using CRISPR‐Cas9 to create PfGEP1 loss‐of‐function lines. These lines failed to undergo male or female gametogenesis, even when stimulated by XA or a temperature drop. The defect persisted despite treatment with the phosphodiesterase inhibitor Zaprinast. Analysis of field samples revealed two GEP1 single‐nucleotide polymorphisms (V241L and S263P) in 12% and 20% of 49 cases. Our findings confirm GEP1's essential role in gamete activation, highlight an XA‐independent function, and support its potential as a transmission‐blocking target. Impact statement For sustainable malaria control, transmission‐blocking drug targets are urgently needed. Work in murine models showed that GEP1 is a candidate. We show complete block of life cycle progression of the human malarial parasite Plasmodium falciparum when GEP1 is deleted, warranting targeted drug development to achieve gamete‐free mosquito blood meals.
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