Deltamethrin and Transfluthrin select for distinct transcriptomic responses in the malaria vector Anopheles gambiae.
Authors: Zoh Marius Gonse , Bonneville Jean-Marc , Laporte Frederic , Tutagata Jordan , Sadia Christabelle G. , Fodjo Behi K. , Mouhamadou Chouaibou S. , McBeath Justin , Schmitt Frederic , Horstmann Sebastian , Reynaud Stéphane , David Jean-Philippe 
Published: May 2023

BackgroundThe widespread use of pyrethroid insecticides in Africa has led to the development of strong resistance in Anopheles mosquitoes. Introducing new active ingredients can contribute to overcome this phenomenon and ensure the effectiveness of vector control strategies. Transfluthrin is a polyfluorinated pyrethroid whose structural conformation was thought to prevent its metabolism by cytochrome P450 monooxygenases in malaria vectors, thus representing a potential alternative for managing P450-mediated resistance occurring in the field. In this study, we used controlled selection to compare the dynamics of resistance between transfluthrin and the widely used pyrethroid deltamethrin in the mosquitoAnopheles gambiae. Then, we investigated the associated molecular mechanisms using target-site mutation genotyping and RNA-seq.MethodsA field-derived line ofAnopheles gambiaecarrying resistance alleles at low frequencies was used as starting material for a controlled selection experiment. Adult females were selected across 33 generations with deltamethrin or transfluthrin, resulting in three distinct lines: the Delta-R line (selected with deltamethrin), the Transflu-R line (selected with transfluthrin) and the Tiassale-S line (maintained without selection). Deltamethrin and transfluthrin resistance levels were monitored in each selected line throughout the selection process, as well as the frequency of theL1014Fkdr mutation. At generation 17, cross-resistance to other public health insecticides was investigated and transcriptomes were sequenced to compare gene transcription variations and polymorphisms associated with adaptation to each insecticide.ResultsA rapid increase in resistance to deltamethrin and transfluthrin was observed throughout the selection process in each selected line in association with an increased frequency of theL1014Fkdr mutation. Transcriptomic data support a broader response to transfluthrin selection as compared to deltamethrin selection. For instance, multiple detoxification enzymes and cuticle proteins were specifically over-transcribed in the Transflu-R line including the known pyrethroid metabolisersCYP6M2,CYP9K1andCYP6AA1together with other genes previously associated with resistance inAnopheles gambiae.ConclusionThis study confirms that recurrent exposure of adult mosquitoes to pyrethroids in a public health context can rapidly select for various resistance mechanisms. In particular, it indicates that in addition to target site mutations, the polyfluorinated pyrethroid transfluthrin can select for a broad metabolic response which includes some P450s previously associated to resistance to classical pyrethroids. This unexpected finding highlights the need for an in-depth study on the adaptive response of mosquitoes to newly introduced active ingredients in order to effectively guide and support decision-making programmes in malaria control.