Ecology and genetics of insecticide resistance in African malaria vectors

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Project summary Title: Ecology and genetics of insecticide resistance in African malaria vectors The current first-line vector control methods rely on pyrethroid-based long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS). Insecticide-resistant vector genotypes are selected, leading to widespread of insecticide resistance in sub-Saharan Africa. The evolution of insecticide resistance is threatening to reverse the global gains in malaria control1,2. Due to the increasing insecticide resistance in sub-Saharan Africa, pyrethroid- based synergized next generation bednets were recently introduced in many African countries to overcome the challenge of insecticide resistance. These nets contain synergist piperonyl butoxide (PBO) which inhibits the activity of pyrethroid detoxifying cytochrome P450 enzymes by forming a metabolite-inhibitory complex with the enzyme. However, little is known about how African malaria vectors respond to PBO exposure at the gene transcription, biochemical and organismal level. It has been shown that in insecticide-sensitive Drosophila that PBO is capable of inducing the expression of the P450 and GST detoxification gene families. The increased production of P450 and GST enzymes by PBO exposure has the potential to increase insecticide tolerance. If this is true to malaria vectors, the impact of PBO on insecticide resistance mitigation is limited. The central objective of this continuation application is to better understand the ecology and genetics of insecticide resistance in the face of pyrethroid synergized nets introduction in the major African malaria vectors in western Kenya where we maintain selected pyrethroid resistant strains and PBO nets are being widely distributed in some counties. To achieve this goal three aims are developed. In aim 1, we will examine the impact of next-generation PBO bednets on vector bionomics and transmission reduction. Data from this will inform the effectiveness of PBO nets in transmission reduction in areas with pre-existing high pyrethroid resistance. In aim 2, we will determine the genetic basis of variations in mosquito phenotypes due to PBO nets. This aim will provide information on importance of the different mechanisms of insecticide resistance that exist in western Kenya which is critical to the development of PBO net deployment strategy. In aim 3, we will determine the response to PBO exposure at the gene transcription and biochemical level in pyrethroid resistant malaria vectors. Data from this aim can provide critical information on the genetic mechanisms and risks of PBO synergist in resistance mitigation in field malaria vector populations with high resistance. Overall, these 3 aims will inform PBO net deployment strategy, impact on transmission reduction and potential risks on its inability to mitigate resistance.