Field-Caught Permethrin-Resistant Anopheles gambiae Overexpress CYP6P3, a P450 That Metabolises Pyrethroids

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Abstract
Insects exposed to pesticides undergo strong natural selection and have developed various adaptive mechanisms to survive. Resistance to pyrethroid insecticides in the malaria vector Anopheles gambiae is receiving increasing attention because it threatens the sustainability of malaria vector control programs in sub-Saharan Africa. An understanding of the molecular mechanisms conferring pyrethroid resistance gives insight into the processes of evolution of adaptive traits and facilitates the development of simple monitoring tools and novel strategies to restore the efficacy of insecticides. For this purpose, it is essential to understand which mechanisms are important in wild mosquitoes. Here, our aim was to identify enzymes that may be important in metabolic resistance to pyrethroids by measuring gene expression for over 250 genes potentially involved in metabolic resistance in phenotyped individuals from a highly resistant, wild A. gambiae population from Ghana. A cytochrome P450, CYP6P3, was significantly overexpressed in the survivors, and we show that the translated enzyme metabolises both alpha-cyano and non–alpha-cyano pyrethroids. This is the first study to demonstrate the capacity of a P450 identified in wild A. gambiae to metabolise insecticides. The findings add to the understanding of the genetic basis of insecticide resistance in wild mosquito populations. Malaria, a disease spread by anopheline mosquitoes, is a global health problem with an enormous economic and social impact. Pyrethroid insecticides are critical in reducing malaria transmission, and resistance to these insecticides threatens current control efforts. With a limited number of public health insecticides available for the foreseeable future, it is vital to monitor levels of resistance to facilitate decisions on when new strategies should be implemented before control fails. For monitoring, simple molecular assays are highly desirable, because they can detect resistance at very low frequencies and should identify the presence of single recessive alleles well before bioassays. An understanding of the mechanisms conferring resistance facilitates the development of such tools and may also lead to novel strategies to restore the efficacy of the insecticide, or the development of new compounds. We set out to identify enzymes that may confer metabolic pyrethroid resistance by comparing levels of messenger RNA between insecticide-selected versus unselected mosquitoes. We caught members of the major malaria vector, A. gambiae s.s. from a highly pyrethroid resistant field population. We found increased transcript levels for a cytochrome P450, CYP6P3, and demonstrate that it encodes for an enzyme that metabolises pyrethroids.

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