Driving a protective allele of the mosquito FREP1 gene to combat malaria

Abstract

Abstract Malaria remains a substantial global health challenge, causing approximately half a million deaths each year1. The mosquito fibrinogen-related protein 1 (FREP1) is required for malaria parasites to infect the midgut epithelium2. The naturally occurring FREP1 Q allele has been reported to prevent parasite infection, while supporting essential physiological functions in the mosquito3. Here we generate congenic strains of Anopheles stephensi, edited to carry either the parasite-susceptible FREP1 L224 or the putative-refractory FREP1 Q224 alleles. The FREP1 Q224 allele confers robust resistance to infection by both human and rodent malaria parasites, with negligible fitness costs. The protective FREP1 Q224 allele can be efficiently driven into FREP1 L224 mosquito populations using a novel linked allelic-drive system that selectively replaces the L224 codon with the parasite-refractory Q224 allele, thereby rendering populations refractory to parasite infection. This antimalaria drive system provides a novel genetic approach to aid in malaria elimination efforts.