Harnessing Genome Editing Tools: Developing New Forms of Genetic Vector Control and Synergizing with Insecticides

Insecticide-based control of mosquitoes has driven the recent huge gains in malaria control, yet growing concerns over insecticide resistance (IR) necessitates both new control approaches and ways to combine approaches that drastically reduce the overall likelihood of resistance. Recent research has demonstrated that a new form of genetic control, called gene drive, can spread a genetic element rapidly in a population and cause its suppression. The gene drive, effectuated through CRISPR-mediated homology-directed repair (HDR), is designed to recognise and disrupt a target sequence in any essential mosquito gene and to copy itself over in the process. Like insecticides, gene drives are also subject to resistance in the form of sequence variation at the target site.

Both forms of control show similarities in the dynamics of selection and spread of resistance yet show completely independent modes of action. After initial suppression, insecticide programs can leave a residual insecticide resistant population that shows drastically reduced genomic variation, thereby making it more susceptible to subsequent control by gene drive. Conversely, it should be possible to engineer gene drives in such a way that after they cause long term suppression, any residual population is newly susceptible to insecticide. This project aims to show proof of principle and feasibility for the wider approach of synergizing insecticides and gene drive to achieve population suppression.

Target-site IR is well-characterised in An. gambiae, classically taking the form of kdr mutations in the voltage-gated sodium channel (VGSC); further to this, population suppression by gene drives have previously been demonstrated in An. gambiae. Conversely, in An. funestus, repair by CRISPR-mediated HDR has not yet been demonstrated, nor has target-site resistance been implicated as a main driver for IR , with resistance instead being conferred metabolically i.e., though cytochrome P450 upregulation. To bridge this knowledge gap and facilitate the implementation of suitable control strategies against both malaria vectors, this project will examine both species in parallel using similar but tailored methodological approaches.