Abstract
Resistance to pyrethroids (the ingredients in bed net insecticides) in the major malaria vector Anopheles funestus is threatening recent gains in the fight against malaria. Here, we established the role of an over-expressed P450, A. funestus CYP6AA1 in insecticides resistance. Transcription profiling of CYP6AA1 across Africa using microarray and quantitative reverse transcription polymerase chain reaction (qRT-PCR) revealed that it is significantly more over-expressed in southern African populations compared to West (Benin) and East African (Uganda). Heterologous expression in Escherichia coli coupled with metabolism assays demonstrated that CYP6AA1 metabolises type I (permethrin) and type II (deltamethrin) pyrethroids, as well as bendiocarb (a carbamate). Transgenic Drosophila melanogaster flies over-expressing CYP6AA1 were significantly more resistant to pyrethroid insecticides, permethrin and deltamethrin compared with control flies not expressing the gene, validating the role of this gene in pyrethroid resistance. In silico modelling and docking simulations predicted the intermolecular receptor-ligand interactions which allow this P450 to metabolise the pyrethroids and bendiocarb. Validation of CYP6AA1 as a pyrethroid resistance gene makes it possible to monitor the spread of resistance in the field where this P450 is over-expressed. Its potential cross-resistance role makes it necessary to monitor the gene closely to inform control programs on molecular basis of multiple resistance in the field.
Highlights
The last 15 years have been a turning point in the fight against malaria in sub-Saharan Africa with the malaria intervention tools helping to avert an estimated 663 million cases of malaria [1]
In A. funestus, the L119F-GSTe2 mutation is widespread in West Africa where 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane DDT resistance is common but absent in southern African populations [9]; and carbamate resistance observed in southern African populations has been attributed to over-expressed P450 CYP6Z1 and a novel N485I mutation in the A. funestus acetylcholinesterase-1 gene; a mutation absent in the East and West African populations [10]
CYP6AA1 was significantly the level observed in Malawi (FC of 5.3) and Zambia (FC of 5.3), consistent with the higher pyrethroids over-expressed in the mosquitoes from Benin (West Africa), compared with FANG, but at a much resistance levels recorded in Mozambique [47]
Summary
The last 15 years have been a turning point in the fight against malaria in sub-Saharan Africa with the malaria intervention tools (vector control and artemisinin-based combination therapies) helping to avert an estimated 663 million cases of malaria [1]. In A. funestus, the L119F-GSTe2 mutation is widespread in West Africa where 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane DDT resistance is common but absent in southern African populations [9]; and carbamate resistance observed in southern African populations has been attributed to over-expressed P450 CYP6Z1 and a novel N485I mutation in the A. funestus acetylcholinesterase-1 gene; a mutation absent in the East and West African populations [10]. This highlights the importance of establishing the spatio-temporal drivers (genes) of resistance in different location/regions to aid in implementing evidence-based control tools and resistance management
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