Wellcome Trust Senior Renewal Fellowship project : elucidating the complex evolution of insecticide resistance in the major malaria vector Anopheles funestus Africa-wide and its impact on control tools

Worrying cases of high resistance levels to insecticides are emerging in major malaria vectors such as Anopheles funestus leading to extensive loss of efficacy of Long Lasting Insecticidal Nets (LLINs) including PBO-pyrethroid nets. Unless such super-resistance is managed, recent gains in reducing malaria transmission could be lost with terrible consequences. Unfortunately, the molecular drivers of this super-resistance remain unknown hindering the design of resistance management strategies to prevent malaria resurgence. This project will elucidate such factors, including the role of a massive increase in metabolic resistance and detect key DNA markers to design diagnostic tools to track and manage this super-resistance before it spreads Africa-wide. Importantly, by detecting the molecular drivers of reduced penetration resistance, likely contributing to observed resistance escalation, this project will help elucidate this under-studied major resistance mechanism.

This is despite its ability to confer resistance across different chemical classes (cross-resistance) which has substantial practical implications for the design of resistance management strategies including rotations. The development of DNA-based diagnostic tools complemented by recent molecular assays will facilitate the use of entomological endpoints to assess the impact of super-resistance on the effectiveness of current and novel insecticide-based tools. This project will also establish the impact of resistance escalation on malaria transmission to predict the potential epidemiological consequences of the rise of super-resistance in Africa. This will allow to better estimate the contribution of resistance to recent increases in malaria cases reported by WHO in 2018.

This research program will provide a deep insight into the molecular processes driving the escalation of resistance in mosquitoes notably the role of a dramatic increase of metabolic resistance, and that from reduced penetration resistance, an alternative resistance mechanism. By pioneering the design of DNA-based diagnostic assays for reduced penetration resistance, this project will help to track and assess the impact of this major resistance mechanism; this is of critical importance  as this mechanism is expected to confer cross-resistance to a broad range of insecticides including novel insecticides recently recommended by WHO.

Furthermore, insecticide resistance genes are often associated with pleiotropic effects on mosquitoes’ life traits which can modify their capacity to transmit malaria parasites to their hosts. By that rationale, this project will take advantage of the recently designed molecular markers and others to identified during this project, to establish the extent to which resistance escalation is increasing the vectorial capacity of resistant mosquitoes to transmit malaria. It will estimate key entomological parameters such as the entomological inoculation rate (EIR) of resistant and susceptible mosquitoes, enabling for the first time to assess the potential epidemiological cost of resistance/super-resistance using entomological indices.