Abstract
BackgroundMalaria control in Africa is dependent upon the use insecticides but intensive use of a limited number of chemicals has led to resistance in mosquito populations. Increased production of enzymes that detoxify insecticides is one of the most potent resistance mechanisms. Several metabolic enzymes have been implicated in insecticide resistance but the processes controlling their expression have remained largely elusive.ResultsHere, we show that the transcription factor Maf-S regulates expression of multiple detoxification genes, including the key insecticide metabolisers CYP6M2 and GSTD1 in the African malaria vector Anopheles gambiae. Attenuation of this transcription factor through RNAi induced knockdown reduced transcript levels of these effectors and significantly increased mortality after exposure to the pyrethroid insecticides and DDT (permethrin: 9.2% to 19.2% (p = 0.015), deltamethrin: 3.9% to 21.6% (p = 0.036) and DDT: 1% to 11.7% (p = <0.01), whilst dramatically decreasing mortality induced by the organophosphate malathion (79.6% to 8.0% (p = <0.01)). Additional genes regulated by Maf-S were also identified providing new insight into the role of this transcription factor in insects.ConclusionMaf-S is a key regulator of detoxification genes in Anopheles mosquitoes. Disrupting this transcription factor has opposing effects on the mosquito’s response to different insecticide classes providing a mechanistic explanation to the negative cross resistance that has been reported between pyrethroids and organophosphates.
Highlights
Malaria control in Africa is dependent upon the use insecticides but intensive use of a limited number of chemicals has led to resistance in mosquito populations
Increased exposure to a limited range of insecticides has led to the emergence of resistance to these compounds [2] which poses a serious threat to the future of malaria control efforts
We show that Maf-S expression correlates with expression of multiple insecticide resistance candidates in the major malaria vector Anopheles gambiae, suggestive of a regulatory role for this transcription factor in insecticide resistance
Summary
Malaria control in Africa is dependent upon the use insecticides but intensive use of a limited number of chemicals has led to resistance in mosquito populations. Increased exposure to a limited range of insecticides has led to the emergence of resistance to these compounds [2] which poses a serious threat to the future of malaria control efforts. Mutations in the voltage-gated sodium channel, the target of both DDT and pyrethroid insecticides, cause the phenotype known as knockdown resistance or kdr. This resistance mechanism is readily tracked through PCR and widely reported, metabolic resistance has a greater operational impact on malaria control [4]. Increased expression of genes involved in each of the detoxification stages has been associated with insecticide resistance in Anopheles mosquitoes [5] but the mechanisms controlling expression of these genes have not been identified
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