Abstract
Malaria control relies heavily on pyrethroid insecticides, to which susceptibility is declining in Anopheles mosquitoes. To combat pyrethroid resistance, application of alternative insecticides is advocated for indoor residual spraying (IRS), and carbamates are increasingly important. Emergence of a very strong carbamate resistance phenotype in Anopheles gambiae from Tiassalé, Côte d'Ivoire, West Africa, is therefore a potentially major operational challenge, particularly because these malaria vectors now exhibit resistance to multiple insecticide classes. We investigated the genetic basis of resistance to the most commonly-applied carbamate, bendiocarb, in An. gambiae from Tiassalé. Geographically-replicated whole genome microarray experiments identified elevated P450 enzyme expression as associated with bendiocarb resistance, most notably genes from the CYP6 subfamily. P450s were further implicated in resistance phenotypes by induction of significantly elevated mortality to bendiocarb by the synergist piperonyl butoxide (PBO), which also enhanced the action of pyrethroids and an organophosphate. CYP6P3 and especially CYP6M2 produced bendiocarb resistance via transgenic expression in Drosophila in addition to pyrethroid resistance for both genes, and DDT resistance for CYP6M2 expression. CYP6M2 can thus cause resistance to three distinct classes of insecticide although the biochemical mechanism for carbamates is unclear because, in contrast to CYP6P3, recombinant CYP6M2 did not metabolise bendiocarb in vitro. Strongly bendiocarb resistant mosquitoes also displayed elevated expression of the acetylcholinesterase ACE-1 gene, arising at least in part from gene duplication, which confers a survival advantage to carriers of additional copies of resistant ACE-1 G119S alleles. Our results are alarming for vector-based malaria control. Extreme carbamate resistance in Tiassalé An. gambiae results from coupling of over-expressed target site allelic variants with heightened CYP6 P450 expression, which also provides resistance across contrasting insecticides. Mosquito populations displaying such a diverse basis of extreme and cross-resistance are likely to be unresponsive to standard insecticide resistance management practices.
Highlights
Malaria mortality has decreased substantially in sub-Saharan Africa over the last decade, attributed in part to a massive scale-up in insecticide-based vector control interventions [1]
Following piperonyl butoxide (PBO)-mediated P450 inhibition, survival of G119S heterozygotes was reduced to approximately 50% and our results show that individuals exhibiting a higher ACE-1 copy number and more copies of the serine allele had a significant survival advantage
Tiassale An. gambiae show exceptionally high-level carbamate resistance and the broadest insecticide resistance profile documented to date
Summary
Malaria mortality has decreased substantially in sub-Saharan Africa over the last decade, attributed in part to a massive scale-up in insecticide-based vector control interventions [1]. As the only insecticide class approved for treatment of bednets (ITNs) and the most widely used for indoor residual spraying (IRS), pyrethroids are by far the most important class of insecticides for control of malaria vectors [2]. Pyrethroid resistance is widespread and increasing in the most important malaria-transmitting Anopheles species [3,4,5] and catastrophic consequences are predicted for disease control if major pyrethroid failure occurs [6]. With no entirely new insecticide classes for public health anticipated for several years [5,6] preservation of pyrethroid efficacy is critically dependent upon strategies such as rotation or combination of pyrethroids with just three other insecticide classes, organochlorines, carbamates and organophosphates [6,7]. With strongly- and multiply-resistant phenotypes documented increasingly in populations of the major
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