No GEP, No Go!

Stopping malaria at the moment it enters the mosquito could prevent the disease from spreading altogether. When a mosquito takes an infected blood meal, the malaria parasite must rapidly transform its dormant gametocytes into active gametes — a shift normally triggered by the mosquito’s cooler temperature and a molecule called xanthurenic acid. Although this step is essential for transmission, the molecular machinery that enables the parasite to sense and respond to these cues is still being uncovered. One protein, GEP1, was recently shown in rodent malaria parasites to be required for this transformation. To determine whether it plays the same role in the human parasite Plasmodium falciparum, the Molecular Parasitology Group (Kai Matuschewski) used CRISPR–Cas9 to disrupt the gene. Parasites lacking GEP1 were completely unable to form gametes, even when exposed to the usual activating signals. The defect could not be bypassed with drugs that boost downstream signaling, revealing that GEP1 performs an essential, previously unrecognized function in gamete activation. Naturally occurring GEP1 variants found in field samples underscore its importance in real-world parasite populations. Together, these findings position GEP1 as a promising new target for strategies aimed at blocking malaria transmission. Check out their FEBS letters Article!

Abstract

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.