PT  - JOURNAL ARTICLE
AU  - Marius Gonse Zoh
AU  - Jean-Marc Bonneville
AU  - Jordan Tutagana
AU  - Frederic Laporte
AU  - Behi K. Fodjo
AU  - Chouaibou S. Mouhamadou
AU  - Christabel Sadia
AU  - Justin McBeath
AU  - Frederic Schmitt
AU  - Sebastian Horstmann
AU  - Stephane Reynaud
AU  - Jean-Philippe David
TI  - Neonicotinoid and pyrethroid combination: A tool to manage insecticide resistance in malaria vectors? Insights from experimental evolution
AID  - 10.1101/2021.06.09.447494
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.06.09.447494
4099  - http://biorxiv.org/content/early/2021/06/10/2021.06.09.447494.short
4100  - http://biorxiv.org/content/early/2021/06/10/2021.06.09.447494.full
AB  - Background The introduction of neonicotinoids for managing insecticide resistance in mosquitoes is of high interest as they interact with a biochemical target not previously used in public health. In this concern, Bayer developed a combination of the neonicotinoid clothianidin and the pyrethroid deltamethrin (brand name Fludora® Fusion) as a new vector control tool. Although this combination proved to be efficient against pyrethroid-resistant mosquitoes, its ability to prevent the selection of pyrethroid and neonicotinoid resistance alleles was not investigated. In this context, the objective of this work was to study the dynamics and the molecular mechanisms of resistance of An. gambiae to the separated or combined components of this combination. A field-derived An. gambiae line carrying resistance alleles to multiple insecticides at low frequencies was used as a starting for 33 successive generations of controlled selection. Resistance levels to each insecticide and target site mutation frequencies were monitored throughout the selection process. Cross resistance to other public health insecticides were also investigated. RNA-seq was used to compare gene transcription variations and polymorphisms across all lines.Results This study confirmed the potential of this insecticide combination to impair the selection of resistance as compared to its two separated components. Deltamethrin selection led to the rapid enrichment of the kdr L1014F target-site mutation while clothianidin selection led to the over-transcription of multiple cytochrome P450s including some showing high homology with the ones conferring neonicotinoid resistance in other insects. A strong selection signature associated with clothianidin selection was observed on a cytochrome P450 gene cluster previously associated with resistance. Within this cluster, the gene CYP6M1 showed the highest selection signature together with a transcription profile supporting a role in clothianidin resistance. Modelling the impact of point mutations selected by clothianidin on CYP6M1 protein structure suggested that the selection of variants affecting its active site can enhance clothianidin metabolism.Conclusions In the context of the recent deployment of neonicotinoids for mosquito control and their frequent usage in agriculture, the present study highlights the benefit of combining them with other insecticides for preventing the selection of resistance and sustaining vector control activities.Competing Interest StatementThe funders have developed and commercialized a product based on the combination of insecticides used within this study and proposed the original hypothesis to be tested. The funders had no role in the study design, data collection, analysis and interpretation of results.