# Plasmodium falciparum gametogenesis essential protein 1 (GEP1) is a transmission‐blocking target

## TL;DR

This study identifies a protein crucial for malaria parasite transmission to mosquitoes and suggests it as a target for drugs to block malaria spread.

## Contribution

The study confirms GEP1's essential role in gamete activation in Plasmodium falciparum and its potential as a transmission-blocking drug target.

## Key findings

- PfGEP1 knockout lines failed gametogenesis even with xanthurenic acid or temperature drop stimulation.
- GEP1 has an XA-independent function in gamete activation.
- Common polymorphisms V241L and S263P were found in 12–20% of field samples.

## 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 statementFor 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.

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.

This study shows Plasmodium falciparum GEP1 is vital for activating sexual stages of malarial parasites even independently of a mosquito factor. Knockout parasites completely fail gamete formation even when a phosphodiesterase inhibitor is added. Two single‐nucleotide polymorphisms (V241L and S263P) are found in 12%–20% of field samples. GEP1 is a strong transmission‐blocking drug target.