Discovery of Knock‐Down Resistance in the Major African Malaria Vector Anopheles funestus

Abstract

A major insecticide resistance mechanism in insect pests is knock‐down resistance ( kdr ) caused by mutations in the voltage‐gated sodium channel ( Vgsc ) gene. Despite being common in most malaria Anopheles vector species, kdr mutations have never been observed in Anopheles funestus , the principal malaria vector in Eastern and Southern Africa, with resistance mainly being conferred by detoxification enzymes. In a parallel study, we monitored 10 populations of An . funestus in Tanzania for insecticide resistance unexpectedly identified resistance to a banned insecticide, DDT, in the Morogoro region. Through whole‐genome sequencing of 333 An . funestus samples from these populations, we found eight novel amino acid substitutions in the Vgsc gene, including the kdr variant, L976F (equivalent to L995F in An . gambiae ), in tight linkage disequilibrium with another (P1842S). The mutants were found only at high frequency in one region and were accompanied by weak signatures of a selective sweep, with a significant decline between 2017 and 2023. Notably, kdr L976F was strongly associated with survivorship to exposure to DDT insecticide, while no clear association was noted with a pyrethroid insecticide (deltamethrin). The WHO prequalifies no DDT products for vector control, and the chemical is banned in Tanzania. Widespread DDT contamination and a legacy of extensive countrywide stockpiles may have selected for this mutation. Continued monitoring is necessary to understand the origin of kdr in An . funestus , and the threat posed to insecticide‐based vector control in Africa.

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