Identifying mechanisms of emergent resistance to new insecticides for molecular monitoring in operational mosquito control programmes

A major contributor to the current stagnation of malaria case rates in Africa is the rapid evolution of insecticide resistance in mosquitoes. Fortunately, repurposed agricultural insecticides are now available, which have a different target to the pyrethroids and organophosphates, the primary classes for treated bednets (ITNs) and indoor residual spraying (IRS). 

Expanded IRS implementation programmes are aiming to combat resistance by incorporating the repurposed neonicotinoid clothianidin, with plans to add the repurposed pyrrole insecticide chlorfenapyr, which is also a component in new dual-treated LLINs. This expanded insecticide arsenal provides an excellent opportunity to manage resistance and provide sustainable control, but resistance can arise quickly and sporadic reports linked with prior agricultural use are beginning to emerge for clothianidin. Management decisions on how to combine or rotate insecticides require detailed understanding of the mechanisms of resistance, which may be complex, and effective markers for molecular surveillance. Linking with a larger MRC project investigating the range of emergent and future resistance to these and other insecticides in Anopheles, the current PhD project would focus on the range of possible sources resistance of resistance affecting the target sites, which for these classes are known to be far more variable than simple substitution polymorphisms, potentially involving RNA editing, alternative splicing and copy number variations. At present these are very poorly understood in mosquitoes, and the project will investigate both Anopheles gambiae and Aedes aegypti to identify cross-genera commonalities and differences in the sources of emergent resistance mechanisms. The project will involve transcriptomic (gene expression) and DNA sequencing, coupled with biochemical and electrophysiological analyses and structural modelling of target site variation, with an end goal to provide candidate resistance marker assays to vector control programmes.

Where does the project lie on the Translational Pathway?

T1 (Basic Research) + T3 (Evidence into Practice)

Expected Outputs

Both T1-oriented publications (genetics, biochemistry) and T3-orietned publications (in journals accessed by control community) will be targeted. Work will combine with and extend from a recently-awarded MRC project grant to the supervisors to generate a portfolio of monitoring and decision making tools to aid programmatic decision making in malaria control primarily, but also potentially for arbovirus control

Training Opportunities

Bioinformatics

Statistical analyses for genomics and transcriptomics

In-vitro functional validation methodologies (biochemistry and electrophysiology)

Diagnostic development and testing

Skills Required

Laboratory skills in molecular biology

Interest in evolutionary and molecular genetics

Strong interest in vector biology and control

Key Publications associated with this project

Grau-Bové X, Tomlinson S, O'Reilly AO, Harding NJ, Miles A, Kwiatkowski D, Donnelly MJ, Weetman D,  Anopheles gambiae 1000 Genomes Consortium (2020) Evolution of the insecticide target Rdl in African Anopheles is driven by interspecific and interkaryotypic introgression. Mol Biol Evol doi: 10.1093/molbev/msaa128.

Yunta CH, Hemmings K, Stevenson Bradley, Koekemoer LL, Matambo T, Pignatelli P, Voice M, Nász S, Paine M (2019)  Cross-resistance profiles of malaria mosquito P450s associated with pyrethroid resistance against WHO insecticides.  Pest. Biochem. Physiol. 161:61-67

Grau-Bové X, Lucas ER, Pipini D, Rippon E, van’t Hof E, Constant E, Dadzie S, Egyir-Yawson A, Essandoh J, Chabi J, Djogbénou LS, Harding NJ, Miles A, Kwiatkowski D, Donnelly MJ, Weetman D, The Anopheles gambiae 1000 Genomes Consortium. Biorxiv  doi: https://doi.org/10.1101/2020.05.18.102343 (currently in revision with PLoS Genetics)

Grau-Bové X, Weetman D (2020) RNA editing: an overlooked source of fine-scale adaptation in insect vectors? Curr. Opin. Insect Sci.  40:48-55

Lucas ER, Miles A, Harding NJ, Clarkson CS, Lawniczak MKN, Kwiatkowski DP, Weetman D, Donnelly MJ; Anopheles gambiae 1000 Genomes Consortium (2019) Whole-genome sequencing reveals high complexity of copy number variation at insecticide resistance loci in malaria mosquitoes. Genome Res. 29:1250-1261.

Deadline: Thursday 11th February 2021; 12:00 noon GMT

Further details on the MRC/DTP and CASE programmes and application guidance and process can be found here