Discovery of knock-down resistance in the major African malaria vectorAnopheles funestus

Abstract

AbstractA major mechanism of insecticide resistance in insect pests is knock-down resistance (kdr) caused by mutations in the voltage-gated sodium channel (Vgsc) gene. Despite being common in most malariaAnophelesvector species,kdrmutations have never been observed inAnopheles funestus, the principal malaria vector in Eastern and Southern Africa. While monitoring 10 populations ofAn. funestusin Tanzania, we unexpectedly found resistance to DDT, a banned insecticide, in one location. Through whole-genome sequencing of 333An. funestussamples from these populations, we found 8 novel amino acid substitutions in theVgscgene, including thekdrvariant, L976F (L1014F inAn. gambiae), in tight linkage disequilibrium with another (P1842S). The mutants were found only at high frequency in one region, with a significant decline between 2017 and 2023. Notably,kdrL976F was strongly associated with survivorship to the exposure to DDT insecticide, while no clear association was noted with a pyrethroid insecticide (deltamethrin). Further study is necessary to identify the origin and spread ofkdrinAn. funestus, and the potential threat to current insecticide-based vector control in Africa.SignificanceKnock-down resistance (kdr) mutations confer resistance to malaria vector control insecticides and pose a grave threat to malaria control. Here, we report the first discovery of kdr inAn. funestus, the principal malaria vector in East and Southern Africa. Kdr inAn. funestusconferred resistance to DDT but not deltamethrin. Based on extensive DDT contamination and unofficial usage in Tanzania, it is possible that kdr emerged because of widespread organic pollution as opposed to through public health efforts. Regardless of origin, the discovery of kdr inAn. funestusis an alarming development that warrants immediate, extensive follow-up and close surveillance to establish the origin, and extent to which it may threaten malaria control inAn. funestus.