Role of cytochrome P450s in insecticide resistance: impact on the control of mosquito-borne diseases and use of insecticides on Earth

Abstract

The fight against diseases spread by mosquitoes and other insects has enormous environmental, economic and social consequences. Chemical insecticides remain the first line of defence but the control of diseases, especially malaria and dengue fever, is being increasingly undermined by insecticide resistance. Mosquitoes have a large repertoire of P450s (over 100 genes). By pinpointing the key enzymes associated with insecticide resistance we can begin to develop new tools to aid the implementation of control interventions and reduce their environmental impact on Earth. Recent technological advances are helping us to build a functional profile of the P450 determinants of insecticide metabolic resistance in mosquitoes. Alongside, the cross-responses of mosquito P450s to insecticides and pollutants are also being investigated. Such research will provide the means to produce diagnostic tools for early detection of P450s linked to resistance. It will also enable the design of new insecticides with optimized efficacy in different environments.

Identifying genomic changes associated with insecticide resistance in the dengue mosquito Aedes aegypti by deep targeted sequencing

“…The majority of detoxification enzymes affected by gene amplifications encoded P450s belonging to CYP9J and CYP6 families that were frequently associated with insecticide resistance in mosquitoes David et al 2013). The overrepresentation of P450s was expected because their overexpression is known to play a key role in pyrethroid resistance, and they are frequently affected by copy number variants (Feyereisen 2006(Feyereisen , 2011.…”

“…Such a resistance mechanism is caused by an increased activity of detoxification enzymes. These detoxification enzymes include cytochrome P450 monooxygenases (P450s or CYPs for genes), carboxy/cholinesterases (CCEs), glutathione S-transferases (GSTs), and UDP-glycosyl-transferases (UDPGTs), although other families can be involved (Hemingway et al 2004;David et al 2013). Their high diversity (roughly 300 genes in Ae.…”

“…Theoretically, metabolic resistance can be the consequence of an increased expression of one or multiple detoxification enzymes capable of metabolizing the insecticide and/or the selection of variants showing a higher insecticide metabolism rate due to conformational modifications. Because overexpression is frequently associated with overtranscription, most candidate genes were identified based on their differential transcription in resistant populations compared to susceptible counterparts using transcriptomics (for review, see David et al 2013). Although subjected to inherent difficulties associated with gene expression studies (e.g., RNA handling and degradation, uncontrolled variation across time, tissues, and populations), these approaches identified several detoxification enzymes overtranscribed in resistant populations, some of them being later validated as pyrethroid metabolizers (for review, see Vontas et al 2012;David et al 2013).…”

“…Because overexpression is frequently associated with overtranscription, most candidate genes were identified based on their differential transcription in resistant populations compared to susceptible counterparts using transcriptomics (for review, see David et al 2013). Although subjected to inherent difficulties associated with gene expression studies (e.g., RNA handling and degradation, uncontrolled variation across time, tissues, and populations), these approaches identified several detoxification enzymes overtranscribed in resistant populations, some of them being later validated as pyrethroid metabolizers (for review, see Vontas et al 2012;David et al 2013). Although these approaches proved their value for identifying metabolic resistance genes, they failed to pinpoint the genomic changes associated to their overexpression.…”

Repellent and mosquitocidal effects of leaf extracts of Clausena anisata against the Aedes aegypti mosquito (Diptera: Culicidae)

“…At present there are only four approved classes of insecticides, namely organophosphates, pyrethroids, carbamates organochlorines, with only two modes of action. This limited number in conjunction with a paucity of approvals for new insecticides for vector control by WHO in the last 30 years, has greatly increased the threat of resistance and reduced the sustainability of chemical insecticides for vector control (David et al 2013). …”